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610 Cards in this Set
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Fick's First Law of Diffusion
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Concentration gradient = deltaC/deltax
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Flux (J)
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Amount of stuff passing through certain cross sectional area in certain amount of time
Proportional to –D * deltaC/deltaX –D = diffusion constant. Minus sign because direction of flux is opposite to direction of gradient. |
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Diffusion distance and time
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1–dimensional – d = sqrt(2Dt)
2–dimensional – d = sqrt(4Dt) 3–dimensional – d = sqrt(6Dt) Diffusion distance depends on sqrt(t) or t depends on distance^2. So, diffusion doesn't work well over long distances. |
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Partition coefficient (beta)
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Beta = Cmem/Caq
>1 – molecule prefers membrane <1 – molecule prefers water Beta changes steepness of concentration gradient in membrane and thus size of flux through membrane |
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Permeability coefficient and flux
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P = Dbeta/deltaX
J = –P(Ci–Co) = PCo – PCi (Influx = PCo, Efflux = PCi) Positive J indicates influx |
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Van't Hoff Equation
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deltaPI = RT deltaC
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Reflection coefficient
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SIGMA = 1– Psolute/Pwater
SIGMA = 1 – Psolute = 0, completely reflected SIGMA = 0 – Psolute = Pwater, not reflected Used to modify vant Hoff equation. |
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Movement of water
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Hydrostatic pressure – high P to low P
Osmotic pressure – low PI to high PI |
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Starling Equation
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Jv = Lp (deltaPI – deltaP) = Lp (sigma RT deltaC(solute)) – deltaP)
Jv = volume flow – volume of water passing through membrane in unit time Lp = hydraulic conductivity/filtration constant, governs permeability of membrane to water. |
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Force driving fluid flow in capillaries
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PIc and Pi drive water into capillary.
PIi and Pc drive fluid out of capillary. Of these, Pc is only systematically changing value. Pc drops through circulation – filtration occurs on arterial side and absorption occurs on venous side. |
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Edema
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Disruption of filtration–absorption balance
Bee sting – disrupts reflection coefficient by changing permeability of capillary. Starvation – disrupts PIc because no albumin. Fluid is not absorbed. Weight lifting – Increases Pc, more filtration. |
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Cell response to permeant solute.
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Cell volume sharply goes down as water exits cell. Original volume gradually replaced.
When permeant solute washed out, cell volume sharply increases as water enters cell. Original volume gradually replaced. Only transient change in cell volume. |
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Cell response to impermeant solute
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Cell volume sharply declines and stays lower because solute cannot equilibrate.
When external solution is restored, cell volume increases to original value. Permanent change in cell volume. |
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Estimating cell volume change in response to change in outside concentration of impermeant solute
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Amount of solute in cell cannot change.
n(NP) = C(NP)*V C(NPinit) * Vinit = C(NPfinal) + Vfinal |
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Ion gradients
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K+ – intracellular
Na+, Cl– – extracellular Ca2+ – extracellular |
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Principle of Electroneutrality
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In any solution, number of positive charges equals number of negative charges.
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Equilibrium and Nernst Equation
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State where no further flux is possible. Potential is described by the Nernst equation:
Ek = RT/F ln ([K+]o/[K+]i) |
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Nernst potentials of common ions
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ECa = 132 mV
ENa = 71 mV ECl = –77 mV EK = –89 mV |
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Why is Calcium not ceiling for Vm?
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Cell membrane is much less permeable to Ca2+ than to Na+ and the concentration is much less.
So flux of Ca2+ is much smaller and doesn't contribute very much. |
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G–H–K
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Describes steady state – no net flow of electrical charges.
Vm = RT/F ln (Pk[K+]o + Pna[Na+]0 + Pcl[Cl–]i)/(Pk[K+]i + Pna[Na+]i + Pcl[Cl–]o) P*concentration = flux Numerator makes inside more positive, denominator makes cell more negative. |
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Current
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Flow of positive charges out of cell
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Driving force
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Vm–Eq
If > 0 – Positive/outward current If < 0 – Negative/inward current |
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Equilibrium vs Steady State
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Equilibrium – no net flux of ions or charges. Stable indefinitely.
Steady state – no net flux of charges but ions continually move. Requires energy to maintain. Steady state fluxes cause concentration gradient to run–down, maintained by Na/K ATPase |
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Donnan Effect
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Total sum of osmotic concentration in cell is always higher than outside because of negatively charged particles and accompanying M+ ions all in cell, so cell is in danger of osmotic crisis – swelling and bursting.
Na/K ATPase pumps Na+ leaking in out. |
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Parts of neuron
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Dendrites receive input
Soma integrates input and transmits to axon hillock passively. If potential reaches threshold, generates and propagates AP. At terminal axon, voltage–gated Ca2+ channels open –> exocytosis. |
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Ion channels
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Hinged door/gate
Integral multipass proteins Increase membrane permeability to ions High selectivity (but not perfectly selective) |
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Voltage–gated Na+ Channels
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4 homologous domains (I–IV) each with 6 alpha helices, S1–S6.
S4 – voltage sensor – has positive charged amino acids every third position that passively responds to membrane potential. P loop connects S5 and S6, contains selectivity filter that lines pore. |
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Voltage–gated K+ Channels
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1/4 length of Na+ Channel
Channel formed by 4 peptide subunits Each subunit contains 6 membrane spanning alpha helices, positively charged S4 and P–loop (selectivity filter) that lines pore. |
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Inward Rectifier K+ Channel
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First to be crystallized
Channel formed by 4 subunits. Each subunit has 2 membrane spanning alpha helices and a connecting P loop, no S4. Each P loop has glycine–tyrosine–glycine sequence as selectivity filter – carbonyl oxygens replace water in associating with K+ ion. |
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Two–pore domain K+ channel
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Channel formed by 2 subunits.
Each subunit has 4 membrane spanning alpha helices and 2 P–loops. |
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Passive Electrical Properties
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Properties with constant values at resting potential of cell.
Includes membrane resistance (constant number of open channels), membrane capacitance, and axial resistance (resistance to current down long axis) |
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Faraday constant
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Amount of charge per mole of electrons
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Current
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Movement of charge past point per unit of time. I = q/t or dq/dt
Positive current is positive charge moving out of cell. |
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Resistance
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Measure of ability of material to oppose flow of current
Depends on geometry and resistivity of material. R = p*l/A p = resistivity, l = length, A = cross sectional area |
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Conductance
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Measure of ease with which current flows through material.
Measured in siemens, proportional to permeability. g=1/R |
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Examining Passive Properties
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Glass pipette with small tip diameter filled with conducting solution.
Measure intracellular potential or pass current. Ag/AgCl eectrode converts current as electrons in device to currents as ions in solution. |
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Effect of passing current
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Membrane potential follows exponential time course to new steady state level.
Outward current = depolarization (more positive) Inward current = hyperpolarization )more negative) |
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IV Curve
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Linear line
Erev (reversal potential) is potential where current changes from in to out. |
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Ohm's Law
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V=IR
I=gV |
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Modifications of Ohm's Law for single–channel and multi–channel
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Microscopic – ik = gammak * (Vm – Ek)
Macroscopic – Ik = gk * (Vm – Ek) gk = N0 * gammak = NT * po * gammak po = gk / (NT * gammak) |
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Capacitance
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Device that can separate or store charges of opposite signs
Parallel plate capacitor has two parallel conducting plates separated by an insulator. q = C*V (capacitance proportional to voltage difference) C is directly proportional to A/d A = area of plates, d = distance between plates |
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Capacitive current and voltage
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dq/dt = C * dV/dt
Capacitive current is proportional to rate of change of voltage. If dV/dt is not 0, there is a capacitive current. |
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Flow of Capacitive Current
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Charges do not cross capacitor. Instead, positive current builds up on one side of capacitor and leaves from the other (leaving buildup of negative charge)
Outwards Ic – positive current, positive dV/dt (depolarizing) Inwards Ic – negative current, negative dV/dt (hyperpolarizing) |
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Difference between ionic and capacitive current
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Capacitive current is:
Caused by change in charge separation rather than ions moving. Proportional to rate of voltage change rather than voltage. |
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Circuit with battery + resistor and capacitor in parallel controlled by switch
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1. When switch is closed, all current goes to capacitor because capacitor has lower resistance and no driving force for ion channels.
Inwards capacitive current hyperpolarizes cell. 2. As membrane potential changes, driving force builds for ion channels so there is less capacitive current. 3. Reaches new steady stage where dV/dt = 0, so there is no capacitive current. All is going through channels. Ionic and capacitive current are in same direction. |
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Potential change over time in response to current pulse
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Voltage follows exponential time course
delta Vm(t) = deltaVm,infinity * (1–e^(–t/Tm)) deltaVm,infinity = constant, final change in voltage t = time in seconds Tm (membrane time constant) = Rm * Cm when both resistor and capacitor are parallel. |
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Time constant
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Tm (membrane time constant) = Rm * Cm when both resistor and capacitor are parallel.
Time constant = time it takes for voltage to change to 63% of final value when current flows. If time constant increases, voltage changes more slowly and AP propagation slows down. Also effects temporal summation. Affected by demyelination and number of open channels. |
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Passive decay of membrane potential with distance
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Delta Vm is largest at point where passing current and decays in either direction away.
Looks like a cartoon bird |
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Length constant
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Take circuit with many smaller circuits with resistor and capacitor (channels)
DeltaVm(x) = deltaV0 * e^(–x/lambda) Lambda = length constant = sqrt(rm/ri) At distance of length constant, voltage reaches 37% of original voltage Length constant is inversely related to internal resistance and positively related to membrane resistance. Length constant is important for spatial summation and speed of AP. Effected by myelination (increased rm) and increasing diameter of nonmyelinated axons. |
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Properties of action potentials
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1. Passive depolarization (decays with distance) to threshold causes AP.
2. AP propagates without decrement. 3. Signal is all–or–none. 4. Refractory period – relative is during repolarization and can be overcome. Absolute threshhold is when interval is further reduced. |
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Voltage clamp
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1. Distance is eliminated as a variable (space clamp).
2. Vm is held constant, thus Ic = 0. 3. Ionic currents are measured as function of time. |
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Action potential under voltage clamp
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Depolarize cell and hold it at 0 mV.
1. Initial spike of outward current – leakage current from non–voltage gated channels. Spike is capacitive current. 2. Rapidly developing inward current = voltage–gated Na+ channels that first activate, then inactivate to form U shape. 3. Steady outward current – voltage–gated K+ channels with only activation phase. |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/39/63/27/15396327_m.png
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Patch clamp
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1. Seal polished glass pipette on surface of cell.
2. Control voltage inside pipette and measure current flow. 3. Recording configurations include on–cell patch, inside–out patch, outside–out patch, or whole–cell. |
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Voltage clamp through single Na+ channels
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At random times, current goes from 0 to some negative value.
Average current found by averaging currents from all channels. Ip(average) looks same as macroscopic current flow. Channel does not open late in depolarization because becomes inactivated. |
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Calculating macroscopic conductance
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gNa = N0 * gamma(Na)
N0 = Nt * p0 –> p0 = open probability gNa = Nt * p0 * gamma(Na) = gNa(max) * p0 or p0 = gNa / gNa(max) |
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Ohm's Law in conductance
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gNa = INa/(Vm–ENa)
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Time dependence of open probability
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1) Na+ channels open
2) Na+ channels close and K channels open |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/39/64/23/15396423_m.png
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Biphasic Na channel gating
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1. Activation – Open activation gate, open inactivation gate.
2. Inactivation – Open activation gate, closed inactivation gate 3. Deactivation – Closed activation gate, closed inactivation gate. 4. Recovery – Closed activation gate, open inactivation gate. Activation gate responds more rapidly to depolarization. Delayed opening of inactivation gate causes refractory period. |
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Action potential conductance cycling
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//fce-study.netdna-ssl.com/2/images/upload-flashcards/39/64/38/15396438_m.png
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Action potential circuit
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//fce-study.netdna-ssl.com/2/images/upload-flashcards/12/58/59/15125859_m.png
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Threshhold
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Voltage where outwards current through open K+ channels equals inwards current through voltage–gated Na+ channels.
If net current is outwards, stimulus is subthreshold because outward current repolarizes. If net current is inwards, stimulus is suprathreshold, inward current depolarizes. |
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AP Propagation and Local Circuit Currents
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Action potential goes down axon because depolarization causes outward capacitive current on either side of impulse.
Na+ channel along axon amplifies V, prevents attenuation. |
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Factors influencing AP Conduction Velocity
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Diameter and myelination – conduction velocity increases with sqrt(d) in nonmyelinated axons and with d in myelinated axons.
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//fce-study.netdna-ssl.com/2/images/upload-flashcards/39/65/94/15396594_m.png
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Why is conduction faster in myelinated cells?
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Increases rm –> increases length constant
Decreases cm –> decreases propagation time constant |
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Hyperkalemic Periodic Paralysis
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AD episodes of weakness/paralysis caused by increase in extracellular K+ (i.e. from exercise)
Caused by defect in skeletal muscle VG Na+ channels. When extracellular K+ increased, HPP muscle depolarizes more. Effect reversed by Na+ channel blocker tetrodoxin. Na+ channels do not inactivate, leading to extra depolarization. Treat by preventing increases in extracellular K+; muscle repolarizes when excess extracellular K is cleared by kidney. |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/39/66/42/15396642_m.png
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Cardiac Action Potential
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Much longer than skeletal muscle AP.
1. VG Na+ channels responsible for rapid upstroke 2. VG Ca2+ channels contribute inward current to maintain depolarization 3. K+ channels (including HERG) help repolarize. |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/12/68/64/15126864_m.png
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Voltage clamp of cardiac AP
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Voltage clamp to depolarize cell.
1. Fast transient inward current generated by voltage–gated Na+ channels. 2. Steady, slowly–developing inward Ca2+ current from L–type channel. |
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Voltage–gated Ca2+ channel
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ECa = 120 mV and channel open probability increases with depolarization. –> Generates AP.
Ca2+ APs have slower upstroke and longer duration than Na+ channel APs because VGCCs open more slowly and incompletely. Blocked by Ca2+ channel blocker, used to reat heart failure, HTN, cardiac dysrhythmias. |
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Calcium Channel Blockers
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Experiment – voltage clamp and measure ICa through VGCCs.
Each pulse after equilibrating with D600 VGCC blocker is smaller – "use–dependent block". Gate does not open so drug does not have access to channel. VGCCs are also blocked by DHPR, also called DHPR receptor. |
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Types of VG Ca2+ Channels
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L–type (CaV1.X) – Large, long–lasting, single channel opening. Inactivates incompletely and slowly.
T–type (CaV3) – Tiny, transient, single–channel openings. Inactivates completely. |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/12/74/58/15127458_m.png
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Bursts of AP in a neuron
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Slow depolarization to threshold (pacemaker depolarization) followed by high frequency burst.
VG K+ channel KA creates pacemaker depolarization and regulates frequency. Ca2+ activated K channel ends spikes. |
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Voltage–gated K Channel (KA)
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Has both activation and inactivation gate.
Current looks like upside down sodium current. Activates at more negative voltage than Na+ channel because involved in threshold. |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/12/75/87/15127587_m.png
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4–AP and KA Channel
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4–AP selectively blocks KA channels.
In presence of 4AP, cell reaches threshhold faster without outwards K+ current. KA channel increases interval between spikes in a burst. |
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Ca2+ activated K+ channel
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Inside–out patch clamp experiment with 3 K+ channels (four current levels).
Channel activated by voltage and increase in intracellular Ca2+. Spontaneous bursts are generated by voltage–gated Ca2+ channels. When intracellular Ca2+ reaches certain level, Ca2+ activated K+ channels allow K+ efflux, repolarizing cell and limiting duration of spike train. |
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ATP–Sensitive K+ Channel
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KATP channel is blocked by high [ATP].
Plasma glucose moved to cytoplasm by GLUT1. ATP blocks KATP, resulting in reduction of outward K+ current and depolarization. Depolarization causes burst of action potentials and Ca2+ influx that releases insulin granules. |
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Sulfonylureas
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T2DM drug that blocks KATP channel leading to insulin release.
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Sur1–Trpm4 channel
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Similar to KATP channel.
Nonselective cation channel blocked by intracellular ATP and by sulfonylureas. |
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EKG and QT interval
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P wave – depolarization of atria
QRS complex – depolarization of ventricle T wave – repolarization of ventricle QT interval measures duration of ventricular AP. |
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Long QT Interval
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Caused by loss of function mutation in hERG K+ channel = longer time to repolarize, longer AP.
Causes arrhythmia called torsades de pointes which can resolve into ventricular fibrillation. |
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TRP Channels
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Transient receptor potential superfamily of channels.
Assemble as tetramers to form nonselective cation channels that also conduct Ca2+ into cell. Includes receptor–operated channels – ligand binding to surface receptors –> PLC –> DAG and IP3. DAG opens TRPC channels. Includes store–operated channels (SOCs) – regulated by level of filling of intracellular Ca2+ stores. TRPV1 – activated by capsaicin and heat. TRPM8 – activated by low temperature and menthol. |
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Electrostatic force and potential energy
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F = 1/4piEo q*Q/r^2
PE = 1/4piE0 q*Q/r = q*V dPE/dx = –F Gradient of potential energy gives rise to the force. |
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Chemical potential energy
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us = us0 + RTln[S]; us0 = constant characteristic of S
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Electrochemical Potential Energy
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PEelectrochem = PEchem + PEelect
us = us0 + RTln[S] + zFV |
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Using electrochemical potential energy for K+
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Intracellular – u = uk0 + RTln[K+] + FVm
Extracellular – u = uk0 + RTln[K+] (Vm = 0 because outside) At equilibrium, uk+in = uk+out Vm simplifies to Nernst potential Ek |
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Na/H exchanger
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Uses Na+ gradient to transport H+ outside.
Na+0 + H+i –> Na+i + H+o uNa0 + uH– –> uNai + uHo [Na]i/[Na+]0 = [H+]i/[H+]0 Electroneutral – Vm is not in equation |
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Cl–/HCO3– exchanger
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Uses Cl– gradient to transport HCO3– out.
Cl–0 + HCO3–i –> Cl–i + HCO3–o [Cl]–/[Cl–]o = [HCO3–]i/[HCO3–]o |
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Reason CO2 cannot travel in blood
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H2CO3 is a very weak acid so cannot store and transport CO2 as H+ and HCO3–.
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Events in blood cell – tissues
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CO2 enters RBC – either
1. attached to Hb–NH2 as carbamino, or 2. uses carbonic anhydrase to generate H2CO3 H2CO3 is then broken down into H+ and HCO3– HCO3– is exchanged for Cl– using HCO3–/Cl– exchanger (exchanger speeds CA by removing product HCO3–) H+ from H2CO3 binds to Hb, converting it to deoxyhemoglobin and removing the O2 which diffuses out of RBC. |
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Events in blood cell – lungs
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Cl– is exchanged for HCO3–
O2 displaces H+ on Hb Freed H+ and HCO3– combine to form H2CO3. Carbonic anhydrase converts H2CO3 to CO2 + H2O. Carbamino also gives up CO2 to form Hb–NH2. CO2 diffuses out of cell. |
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Time for CO2 and O2 exchange
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Occurs in 0.75 sec, which is time it takes for RBC to pass alveolus (0.3 um)
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Contents of RBC
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5 million copies of carbonic anhydrase
1 million copies of Cl–/HCO3– exchanger |
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CO2 fate in RBC
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10% dissolved CO2
20% Carbamino compound 70% HCO3– |
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Polar vs Nonpolar Solute Permeability
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Polar solutes cross membrane slowly, nonpolar solutes cross membrane rapidly.
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Kidney water permeability
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1. ADH acts on G–PCR in cortical collecting duct (CCD)
2. cAMP stimulates temporary insertion of AQP into CCD membrane. 3. Increased H20 reabsorption – concentrates urine. Defect = diabetes insipidus |
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Types of mediated transport
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Channels/pores
Gated channel (one gate) – closed and open conformations Carrier (two gates) – exofacial, occluded (transition), and endofacial conformations |
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What determines transport rate?
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1. Number of channels or carriers
2. Chemical/electrochemical driving force 3. Turnover number (cycling rate or single channel conductance) |
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Facilitated diffusion
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Carrier–mediated
Cannot generate steady concentration gradient. Members of major facilitator super family |
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GLUT1
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Found in RBCs and choroid plexus/ependyma
12 transmembrane segments Can cycle when either glucose–bound or empty Specificity – D–glucose and D–galactose >> L–glucose, D–ribose Competitive (D–Glu vs D–Gal) or noncompetitive inhibition (phloretin) Reversible, regulated, saturation M–M kinetics Vectorial transport Counter–transport – if Glu/Gal cell placed in Glu bath, Glu in cell goes up and Gal in cell goes down initially as Gal transported out. Defect causes hypoglychorachia (low CSF glucose), convulsions, microcephaly |
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Regulation of GLUT transporters
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ADH (AQP2)
Insulin (GLUT4) Transporter phosphorylation Substrate inhibition |
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Examples of Secondary active transporter
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Na+/H+ exchanger
Cl–/HCO3– exchanger Na+/I– cotransporter (intestine, thyroid) – absorbs iodine in diet and moves into thyroid Na+/monocarboxylate cotransporter (intestine) – transports lactate, pyruvate, nicotinate. Expression correlates with colorectal cancer survival. Na+/serotonin cotransporter (neurons) – target of SSRIs such as Prozac which prolong serotonin action. |
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SGLT–2
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Na+–Glucose symporter that reabsorbs glucose in proximal part of proximal tubule.
Mechanism – 1. Extracellular gate opens. 2. Na+, then Glu enters. 3. Extracellular gate closes forming transition state. 4. Intracellular gate opens, releasing solute. Only unbound or fully–loaded carriers can cycle between exofacial and endofacial states. [G]i/[G]0 = 100 <– REVIEW CALCULATION |
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SGLT–1
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2Na+–1Glucose symporter – reabsorbs glucose on apical side of distal part of proximal tubule, intestine.
Allows removal of virtually all glucose but may create osmotic issue because of glucose in epithelia. GLUT2 used as safety valve in basolateral membrane (along with Na/K ATPase). [G]i/[G]0 = 10,000 <– REVIEW CALCULATION |
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Oral Rehydration Therapy
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To treat osmotic diarrhea use oral glucose/Na+ solution – water follows after absorption by SGLT2 and SGLT1.
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GLUT1 deficiency
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Hypoglycorachia, convulsions, microcephaly
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GLUT2 deficiency (Fanconi–Bickel syndrome)
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Impaired glucose tolerance, hypoglycemia, excess hepatic glycogen storage
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Glucose–Galactose Malabsorption
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SGLT1 defect – severe osmotic diarrhea (sugar and water stay in gut) and mild glycosuria because most glucose is still absorbed by SGLT2.
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Renal glycosuria
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SGLT2 deficiency. Severe glycosuria but normoglycemia (can still absorb glucose in gut)
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Na+/Ca2+ Exchanger
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Moves 1 Ca2+ out and 3 Na+ in. Free exchanger or fully bound exchanger cannot cycle.
Responsible for most of Ca2+ extrusion in cardiac myocytes and maintains Ca2+ entry to maintain tone in smooth muscle. [Ca2+]i is 0.0001 of [Ca2]o |
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Exchanger Reversal Potential
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Vm at which there is no exchanger–mediated net flux of ions (Na+ and Ca2+ for Na/Ca2+ exchanger)
Ena/ca = 3ENa – 2ECa Positive reversal potential brings Ca2+ out Depolarization brings Ca2+ in ?? |
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Tertiary Active Transport of Organic Anions
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Basolateral side –
Na/K pump Na+/dicarboxylate cotransporter to transport in alpha ketoglutarate OA/alphaKG antiport imports in organic anions. Apical side – organic anions exit cell from apical side. |
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SGLT
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SGLT1 – kidney and gut
SGLT2 – kidney |
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Three classes of ATPases
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F1 F0 ATPases
V–type ATPases – lysosomes and secretory P–type ATPases – form phosphorylated intermediates |
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Sodium pump activity
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Accounts for 75–85% of total ATP in brain.
Highly active in kidney – 99% of Na+ load reclaimed. |
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Sodium pump structure
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Alpha–beta dimer
Alpha is catalytic subunit with Na+, K+, MG2+, ATP, EO binding sites, as well as ATPase activity and phosphorylation site. Alpha has 10 transmembrane domains, beta had 1 Beta serves as chaperone for alpha and is required for enzymatic activity. |
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Mechanism of Sodium Pump
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1. Int gate open, ext gate close – Na+ binds, K+ leaves
2. Int gate closed, ext gate closed – ATP hydrolysis and conformational change. 3. Int gate closed, ext gate open – Na+ released, K+ binds. 4. Int gate closed, ext gate closed – pump dephosphorylates. |
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Isoforms of Na+ Pump
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alpha 1 – expressed in all cells and distributed throughout cell surface. Maintains low intracellular [Na+].
alpha 2 = expressed in muscle, glia, and some neurons alpha 3 – many neurons alpha 4 – sperm (Cmns) alpha 2 and alpha 3 are confined to PM–sarcoplasmic/endoplasmic reticulum domains and colocalize with SERCA and NCX1. |
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Regulation of Na+ Pump
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1. FXYD proteins
2. Endogenous Cardiotonic Steroids (EO) |
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FXYD proteins
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Phe–X–Tyr–Asp sequence
e.g. Phospholemman (PLM or FXYD–1), sometimes called gamma subunit. Has single trans–membrane domain, binds to alpha subunit. Phosphorylation increases pumps affinity for Na/K to increase Na+ transport. Phospholamban is analogue for SERCA. |
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Endogenous Ouabain
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Hormone synthesized in adrenal cortex
Binds to outer vestibule and... 1) Inhibits Na+ pump 2) Activates protein kinase cascades and modulates Ca2+ transporter expression (EO but not digoxin) |
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Functions of Na+ pump
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1. Maintains low [Na+] and high [K+]. Helps maintain homeostasis and cell volume and avoid swelling. Also permits action potentials.
2. Maintains Na+/Cl– homeostasis and blood volume. 3. Generates electrochemical potential which makes cell living battery. 4. Net outer charge movement generates small electrogenic current of 1–2 mV in steady state. Electrogenic current responsible for after–hyperpolarization. AHP is abolished by ouabain. Ouabain diminishes relative refractory period. |
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Role of alpha 2 ouabain–binding site
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1. alpha 2 R/R mice are resistance to ouabain–induced and ACTH–induced HYTN. Immunoneutralization of ouabain also attenuates HTN
2. Pregnant alpha 2 R/R mice have lower blood pressure. 3. Blood pressure overload–induced cardiac hypertension and failure are delayed and attenuated in alpha 2 R/R mice. 4. Skeletal muscle exercise endurance is enhanced in alpha 2 R/R mice. Ouabain maintains blood pressure |
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Regulation of EO
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Release from adrenals is regulated by hypothalamus renin–angiotensin system.
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Action of EO
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EO activates Na+ pump–protein kinase signaling cascade and modulates protein expression.
Increases NCX1 expression in arteries and heart, increased arterial contraction, decreased cardiac contraction. |
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EO Action in Arteries
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Acute pathway – decreases alpha 2 Na+ pump, increases Na+ in cytoplasm. Na+ in exchanged for Ca2+ (NCX1) so Ca2+ goes up in cytoplasm and SR leading to arterial contraction.
Chronic pathway – alpha 2 Na+ pump acts through protein kinases to increase NCX1 (increased cytoplasmic Ca2+) and SERCA2 expression (increased SR calcium) Vm = –35mV in arteries. So driving force (Vm–ENa/Ca) > 0 = more Ca2+ entry. |
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EO Action in Heart
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Acute pathway – decreases alpha 2 Na+ pump, increases Na+ in cytoplasm. Na+ in exchanged for Ca2+ (NCX1) so Ca2+ goes up in cytoplasm and SR leading to arterial contraction.
Chronic pathway – alpha 2 Na+ pump increases Na+ in cytoplasm. NCX now works opposite way to pump Ca2+ out and bring N in. Decreased Ca2 in cytosol and in SR causes decrease in cardiac contraction. Vm = –70 mV in heart. So driving force <0 and Ca2+ is extruded. |
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Signals leading to gastric acid secretion
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Meal –> Vagus nerve (ACh) –> Pyloric glands (gastrin) –> Enterochromaffin–like cells (Histamine) –> Parietal cells (Histamine receptors) –> Gastric acid secretion
Parietal cells employ H,K–ATPase to secrete isotonic HCl which is diluted to pH3 in lumen. pH < 5 activates cleavage of pepsinogens to pepsins. |
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Histamine and gastric acid secretion
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Histamine activates fusion of tuberovesicles with H,K–ATPase into parietal cell apical membrane.
To terminate activity, H,K ATPase is retrieved and recycled. |
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Secretion of chloride in HCl secretion
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Chloride is provided by basolateral Cl–/HCO3– exchanger and then secreted apically by chloride channel. K+ is recycled by apical K+ channel.
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H+/K+ ATPase location
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Parietal cells of small intestine
Renal CCD intercalated cells |
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Treatment of heartburn and reflux
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Antacids – neutralize acids
Histamine H2 Receptor blockers (Tagamet) H+,K+ ATPase inhibitors – prilosec |
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Familial Hemiplegic Migraine type 2
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alpha 2 Na+/K+ pump loss of function (astroglia, myocytes) – fetal convulsions, headache, hemiplegia.
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FHM type 1
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CaV2.1 Ca2+ channel gain of function (neurons) – spreading depression
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FHM type 3
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NaV1.1 Na+ channel gain of function (neurons) – convulsions and ataxia
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Rapid onset Dystonia with Parkinsonism
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alpha 3 Na+ pump (neurons) – spasmodic, involuntary movement. Raise Na+ in cell, thus raising Ca2+
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Brody's Disease
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SERCA1 (skeletal muscle SR) .Stiff man syndrome – slow muscle relaxation after exercise because Ca2+ taken back into SR slowly.
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Menke's Disease
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ATP7A Cu ATPase (intestine and kidneys). ATP7A transfers Cu2+ from basolateral membrane to plasma to absorb (intestine) and reabsorb (kidney) Cu.
Neurogeneration, kinky, steely hair |
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Wilson's Disease
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ATP7B Cu ATPase (liver, brain).
ATP7B pumps Ca2+ into bile ducts for excretion. Hepatitis, cirrhosis, psychosis. |
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After–hyperpolarization
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Explained by electrogenic, hyperpolarizing effect of Na/K exchanger. Abolishing exchanger abolishes AHP.
AHP is involved in relative refractory period |
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Epithelia functions
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Protective barrier and vectorial transport
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Tight junction
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Acts as barrier and polarizes apical and basolateral sides of cell
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Sides of cell
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Apical – luminal/mucosal
Basolateral – interstitial, serosal, peritubular |
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Common properties of epithelia
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1) Na/K ATPase localized only to basolateral membrane.
2) K+ channel is dominant on basolateral membrane – makes membrane potential near Ek 3) Large inward Na+ elecrochemical gradient, exploited by apical Na+ transporter, exchanger, or symporter. 4) Polarized distribution of transport proteins in series. |
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NaCl absorption in frog skin
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Apical side – Na+ movement down concentration gradient into cell via ENaC.
Basal Na/K ATPase moves Na+ further into interstitium. K+ is recycled by being pumped out by basal channel. Cl– follows into interstitium by paracellular transport. Apical membrane is depolarized by Na+ entry; basolateral membrane is repolarized by Na/K ATPase. Negative transepithelial potential causes Cl– to follow Na+ past basolateral membrane by paracellular transport. |
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NaCl absorption in kidney collecting duct
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Apical side – ENaC, K+ channel
Basolateral side – Na/K ATPase, K+ channel K+ mostly passed through apical membrane because of negative transepithelial potential. Diuretic drug blocks ENaC, preventing salt reabsorption. Collapses electrochemical potential so K+ now has less force across apical membrane – K+ excretion is prevented. (K+ sparing) |
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Na–Glucose absorption
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Apical Na/Glucose coporter.
Basal Na/K ATPase and GLUT2 transporter. Kidney reabsorbs nearly all glucose filutered in glomerulus. Oral rehydration therapy contains Na+ and glucose which is absorbed along with water to treat secretory diarrhea. |
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Secretion of NaCl
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Apical – Cl– transporter
Basal – Na/K ATPase, Na+/K+/2Cl–, K transporter Sodium gradient used to drive K+ and Cl– movement across basolateral membrane. K+ is recycled back across basolateral by K+ transporter, Na+ is recycled by Na/K ATPase Apical Cl– transporter creates negative transmembrane potential which draws Na+ to lumen via paracellular transport. |
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Tight and leaky epithelia
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Tight epithelia – high concentration gradient, low transport rate
Leaky epithelia – low concentration gradient, high transport rate |
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Regulation of epithelial transport
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1. Increase synthesis or degradation of transport proteins
2. Post–translational modifications e.g. phosphorylation 3. Trafficking – recruitment and retrieval of channels to and from PM 4. Changes in paracellular pathway. |
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Cystic Fibrosis
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DeltaF508 defect in CFTR Cl– channel – cannot secrete Cl–. Airway clogs.
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Isoosmotic Water Transport
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Can use AQPs to transmit water down very small concentration gradient. Showed to exist because engineered into frog eggs and put into aqueous environment – eggs blew up.
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Structure of skeletal muscle
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Bundles of actin thin and myosin thick filaments form myofibrils. These form sarcomeres of alternating light and dark bands extending from Z–line to Z line, which are in register forming striations.
SR surrounding each myofibril and T–tubule invaginations of PM form triads. |
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Structure of cardiac muscle
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Striated, form sarcomeres in register with eachother. Many mitochondria.
Every myocyte is in contact with blood vessel. Electrically coupled via gap junctions in intercalated discs where two myocyes meet – allows synchronicity. |
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Cross–bridge cycle (skeletal and cardiac)
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When Ca2+ is present:1. ADP and Pi bound.
2. Pi released – power stroke. 3. ADP released – RLS 4. Binding of ATP – cross bridge detaches 4. ATP hydrolysis – myosin head recocks |
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Structure of smooth muscle
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Found in walls of hollow organs – arterioles, small intestine, bladder
Thick and thin filaments organized in randomly arranged, obliquely oriented bundles – no striation Thin filaments attached to dense bodies composed of alpha–actinin (analogous to Z line) Dense bodies in adjacent cells connect to allow force transmission |
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Function and orientation of smooth muscle
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Blood vessels – bundles perpendicular to long axis so contraction causes reduction of diameter.
GI tract – bundles parallel to long axis so contraction causes peristalsis. Bladder – bundles randomly oriented, contraction causes shrinking and ejection of contents. |
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Control of contraction in smooth muscles
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1. Ca2+ enters cell from SR or surface membrane.
2. Ca2+ binds to calmodulin. 3. Calmodulin activates MLCK. 4. MLCK phosphorylates regulatory light chain, permitting cross bridge cycling. |
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Other molecules ismooth muscle contraction
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MLCP opposes MLCK by dephosphorylating regulatory light chain – promotes relaxation.
PKA inactivates MLCK by phosphorylating MLCK – promotes relaxation. Rho–associated protein kinase inactivates MLCP by phoshporylase – promotes contraction. |
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Cross bridge cycling in smooth muscle
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MLCK phosphorylates regulator light chain, allowing myosin head to bind to actin filament.
1. ADP and P are bound. 2. P unbinds – power stroke. 3. ADP unbinds – RLS. 4. ATP binds. 5. ATP hydrolysis – myosin head recocks, then binds. At any time, myosin light chain can be dephosphorylated – causes crossbridge to remain attached for longer = increases tone. Cycle stops because myosin and actin can no longer bind. |
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Contracture
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Caused by increasing extracellular K+ concentration to depolarize cell, results in generation of force.
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Could diffusion of Ca2+ from surface explain EC coupling?
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No – diffusion from surface is too slow
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SR proteins
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1. SERCA – ATP dependent pumping of Ca2+ into SR.
2. RyR – Transmits Ca2+ from SR to lumen. 3. Calsequestrin – Ca2+ buffer to increase storage. |
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Triad in skeletal muscle
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Composed of T–tubule flanked by terminal cisternae of SR.
DHPR tetramers in T tubule associate with every other Ryr tetramer in SR (only in skeletal muscle) "Feet protein" are cytoplasmic domains of RyR seen in triad. |
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DHPR and RyR coupling
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DHPR has positively charged S4 voltage sensor which is mechanically linked to RyR plug.
Usually – negative membrane potential places voltage sensor at inside surface of membrane. Depolarization – voltage sensor moves towards outside of membrane, pulling on plug and opening RyR. |
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Summary of skeletal muscle EC coupling
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1. AP propagates on surface and in T tubule.
2. T tubule depolarizes, opening RyR. 3. Ca2+ flows from SR into cytoplasm. 4. Ca2+ binds troponin C and contraction begins. 5. Eventually SERCA sequesters Ca2+ back into SR with calsequestrin –> relaxation. Muscle can contract without extracellular Ca2. |
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Differences in E–C coupling in cardiac muscle
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Diads of single RyR and DHPR.
SR is associated with both surface memrane and T–tubules. RyR and DHPR are not closely paired tetramers. |
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E–C Coupling in cardiac muscle
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1. AP propagates on surface and in T–tubule
2. L–type Ca2+ channels on surface open, admitting Ca2+ 3. Ca2+ binds to troponin C OR binds to and opens RyR (Ca2+ induced Ca2+ release). 80% Ca2+ released from SR, 20% from ECF. 4. Relaxation – 80% SERCA (back to SR), 15% NCX and 5% PCMA (PM Ca2+ pump) |
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Smooth muscle structure
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Lakc striations
Actin thin and myosin thick filaments run obliquely as bundles and are not in register with eachother. Found in walls of hollow organs – blood vessels (circularly), GI tract (longitudinally), bladder. |
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Tonic vs Phasic
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Phasic – relaxes most of time, contracts briefly – e.g GI tract or bladder
Tonic – contracts most of the time, relaxes briefly – e.g. esophageal sphincter |
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Single–unit vs Multi–unit smooth muscle
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Single–unit – mostly phasic. All cells behave as one unit interconnected by gap junctions – e.g. GI tract.
Multi–unit – mostly tonic. Each cell contracts and relaxes independently – e.g. vascular smooth muscle. |
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EC Coupling in Phasic Smooth muscle
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Calcium–induced calcium release.
Rhythmic Vm changes –> LVGCs –> RyR –> Phasic contraction |
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EC Coupling in Tonic Smooth Muscle
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No APs, few VG Na+ channels
Small resting membrane potential (–55 to –40 mV) Open LVGCs are sensitive to small Vm changes and cause graded depolarization and hyperpolarizations –> graded contraction and relaxation |
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Myogenic tone experiment
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Exp – Seal artery with canula on one side and surround with physiological salt solution. Artery observed to contract at steady state.
Myogenic tone is Ca2+ dependent – does not occur in Ca2+ free solution When treated with DHP, constriction does not occur – LVGCs are also required. Contraction involves increase in [Ca2+] |
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Myogenic tone mechanism
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Stretch/pressure –> opening of cation channels –> depolarization –> Opening of LVGCs –> Ca2+ entry –> Myogenic tone
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Neural excitation of smooth muscle
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No synapses – axons form varicosities with variety of neuroteansmitters (skeletal only uses ACh)
Different types of smooth muscles express different receptors. |
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Parasympathetic and sympathetic effects on smooth muscle
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Parasympathetic (ACh) activates GI smooth muscle contraction and relaxes vascular smooth muscle.
Sympathetic (NE, ATP, NPY) relaxes GI smooth muscle and activates vascular smooth muscle contraction. |
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Hormone signals on smooth muscles
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Angiotensin II – vasoconstriction
EO – vasoconstriction NO – vasodilation |
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Mechanism of NE
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NE –> alpha 1 GPCR –> alpha(GTP) –> PLC –> IP3 and DAG
IP3 binds and opens IP3R on SR, allowing Ca2+ release and binding to calmodulin. DAG –> ROC –> Ca2+ entry from EC fluid Intracellular Ca2+ can lead to contraction, can be pumped back into SR, or can depolarize cell, activating LVGCs. |
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EC coupling in large and small arteries
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Large arteries have high sympathetic pharmacomechanical innervation.
Small arteries have dominant myogenic contraction. |
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Regulation of Ca2+ levels
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SERCA is not as potent in smooth muscle.
Ca2+ depletion causes SR to signal opening of store operate channels on PM. NCX can also reverse direction to bring Ca2+ in and Na+ out. PM Ca2+ ATPASE (PMCA) and NCX pump Ca2+ out of cell. Sources of Ca2 are: LVGCs, ROCs, SOCs, NCX, RyR, and IP3R. |
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Regulation of Ca2+ sensitivity
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Ca2+–Calmodulin activates MLCK which phosphorylates regulatory light chain.
MLCP dephosphorylates myosin regulatory light chain. |
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NE, NO, and smooth muscle
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NE –>>> PKA. PKA phosphorylates and inhibits MLCK –> relaxation of GI smooth muscle
NE –> G12/13 –> LARG –> RhoA –> ROK ROK phosphorylates and inactivates MLCP –> contraction of vascular smooth muscle. NO –> cGMP –> PKG PKG phosphorylates and inhibits RhoA, preventing inactivation of MLCP leading to vasodilation. |
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Twitch vs tetanus
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Twitch – single contraction and relaxation by one AP
Tetanus – Large contraction caused by high frequency train of APs |
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Why is there delay between skeletal AP and force generation?
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Series elastic elements (tendons) must be stretched before force transmits.
There are also parallel elastic elements to prevent too much force – sarcolemma, cytoskeleton. |
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Why doesn't twitch develop maximum force?
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Ca2+ dissociates from troponin before series elastic elements are stretched.
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Varying force of skeletal muscle
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Increase number of motor units recruited
Increase stimulation frequency |
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What causes delay between AP and force development?
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Series elastic element must be stretched before fibers generate force.
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Isometric vs isotonic contraction
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Isometric – Force generated at constant length
Isotonic – Shortening occurs at constant force (normal contraction). |
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Apparatus for studying isotonic contraction
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Place muscle on one end of lever and load on other end to stretch muscle.
When muscle is stretched, place stop and stimulate muscle to generate force at fixed length. |
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Length–Tension Curve
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L0 = optimal length = length at maximum tension.
Sliding Filament Theory: tension is proportional to number of crossbridges generated. Therefore: Too long fiber length – less overlap between myosin and actin so fewer crossbridges form. Too short fiber length – myosin forms crossbridge with actin from opposite side of sarcomere. |
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How to generate isometric contractions
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Add afterload to apparatus.
Muscle must develop tension (isometric contraction) before it is able to oppose afterload (isotonic contraction). |
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Mixed isometric and isotonic contraction
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When afterload is added, muscle develops tension (isometric) until enough tension is developed to lift load, at which point isotonic contraction occurs.
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Mixed isometric and isotonic contraction
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//fce-study.netdna-ssl.com/2/images/upload-flashcards/18/90/39/15189039_m.png
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Force Velocity Curve
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Maximum velocity of shortening (V0) occurs with no load because all crossbridges are available for cycling.
Velocity of shortening is proportional to rate of crossbridge cycling and to myosin ATPase activity. |
//fce-study.netdna-ssl.com/2/images/upload-flashcards/18/95/34/15189534_m.png
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Types of skeletal muscle fibers
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1. FF – Fast twitch, fatiguable. Maximum force
2. FR – Fast twitch, fatigue resistant. 3. S – Slow twitch, fatigue resistant |
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Fatigue
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Decrease in force with repetitive train of tetanic stimuli
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Fatigue index
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Ratio of tetanic force after 2 minutes repeated stimulation to force generated by first tetanus
FF: FI < 0.25 FR: FI > 0.75 S: FI = 1 |
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Recruitment of fibers
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1. S (posture), 2. FR (walk, run), 3. FF (gallop, jump)
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Varying force generation in skeletal muscle
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1. Recruit more motor units
2. Repetitive stimulation (twitches and tetanus) 3. Muscle stretch (length–tension curve) 4. Recruit different muscle fiber types |
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Time course of APs, [Ca2+]i, and force development in skeletal and cardiac
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1. Cardiac muscle has longer APs
2. In cardiac muscle, [Ca2+] and force returns to normal before AP finishes. Prevents summation/tetanus and creates rhythmic contractions |
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Comparison of length–tension relationships in skeletal and cardiac muscle
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Similar curves but active tension falls steeply in cardiac muscle.
Increase in passive tension occurs at much shorter sarcomere lengths in cardiac muscle. |
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Passive force
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Resistance developed when muscle is stretched.
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Frank Starling Relationship
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Increase in ventricular end–diastolic volume causes increase in ventricular pressure during systole and diastole.
Systolic pressure falls after a certain increase in ventricular end–diastolic volume. |
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Comparison of Force–Velocity Relationship in Skeletal and Cardiac muscle
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Velocity of shortening is much slower in cardiac muscle and develops at much smaller force. Otherwise same shape.
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Positive inotropic effect
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Sympathetic stimulation
NE –> Beta adrinergic receptor –> cAMP –> PKA –> phosphorylates DHPR receptors –> increased Ca2+ Positive inotropic effect – not seen in skeletal because depends on SR. |
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Length tension curve in smooth vs skeletal
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Similar shape as skeletal muscle.
However, length of muscle does not correlate with sarcomere length – must use relative tension and relative length. Cannot use single fiber for experiment, must use whole artery. |
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Force–velocity relationship in smooth vs skeletal
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Force and velocity are both less than one–tenth in smooth muscle.
Velocity is linearly proportional to phosphorylation of regulatory light chain. Force is nonlinearly related to phosphorylation of regulatory light chain (maximum force at 60% phosphorylation) |
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Time course of [Ca2+], MLC phosphorylation and force in phasic smooth muscle
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Brief stimulation causes spike in [Ca2+] and phosphorylation. Force is generated transiently.
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Time course of [Ca2+], MLC phosphorylation and force in tonic smooth muscle
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Sustained stimulation causes spike in Ca2+ and phosphorylation which then fall to a higher than baseline level. Force increases and remains at a high value for duration of stimulation.
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How is [Ca2+] level maintained in smooth muscle cells?
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Experiment – Load rat artery with fluorescent indicator of Ca2.
Give alpha 1 adrinergic agonist and plot Ca2+ changes of individual cells. Ca2+ originally increases and then drops in most cells but increase is maintained in some cells. |
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How does smooth muscle maintain tone?
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Longer step duration (ts) and 4–fold greater duty cycle ration (ts/tcycle)
Ts is time between attachment and detachment of myosin head. Smooth muscle has myosin SM–A which has high ADP affinity –> slow cross–bridge cycle. If myosin light chain is dephosphorylated, cycling becomes very slow. |
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Muscle efficiency
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Work performed per mole ATP consumed. Skeletal muscle is 4x more efficient
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Muscle economy |
Amount of maintained stress (tone) at given rate of ATP consumption. Smooth muscle is 300–fold more economical than skeletal muscle |
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Functions of CV System
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1) Meet body's metabolic needs – deliver O2 (12 fold during exercise) and remove CO2/metabolic byproducts
2) Maintain blood flow to brain and heart 3) Maintain blood pressure to drive renal filtration 4) Distribute nutrients, immune cells, hormones 5) Control core temperature |
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Importance of constant MAP
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Allows tissues to regulate own flow by adjusting resistance
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Types of vessels
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Large arteries – conduit vessels
Arterioles – resistance vessels Capillaries – exchange vessels Veins – return vessels |
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Cardiac output
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Flow out of aorta.
CO (L/beat) = HR (beat/min) * SV (L/beat) |
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Fick's Law
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VO2 = deltaAVO2 * CO
VO2 – rate of O2 consumption deltaAVO2 – difference in O2 content between arterial and venous system For individual tissue, replace CO with flow (q) and use deltaAVO2 for tissue. |
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Pressure
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Force/Area
Measured in mmHg Total pressure includes hydrostatic pressure and other (respiratory, muscular, etc) |
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Hydrostatic Pressure
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P = pgh, p = density
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Flow vs Flow Velocity
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Flow Q = Volume/Time – constant throughout system
Flow velocity V = Q/A – decreases in wide part |
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Ohm's Law for Fluid Flow
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V = IR
deltaP = Q * R, Q = flow, R = resistance |
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Calculating total hydraulic resistance
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Series – sum individual resistances
Parallel – 1/RT = 1/R1 + 1/R2 + ... + 1/Rn |
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Poiseuille's Equation – Effect of tube length, radius, and viscosity on flow
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Q = (Pi–Po) * pi*r^4 / 8nl = deltaP / R
R = 8nl/pi*r^4 Flow is directly proportional to r and deltaP and inversely proportional to viscosity and length. |
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Laminar vs Turbulent Flow
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Laminar flow – silent with parabolic distribution of flow velocity. Obeys Poiseuille's equation.
Turbulent flow – Noisy with chaotic distribution of flow velocity. |
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Compliance
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Ability to distend vessel based on pressure. Ratio of change in volume per unit change in pressure. Analogous to capacitance
C = deltaV / deltaP = deltaV / pgdeltah Short tubes have high compliance |
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Pulse pressure
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Systolic pressure (SBP) – diastolic pressure (DBP)
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Mean arterial pressure
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(1/3 * Pulse Pressure) + Diastolic Pressure
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Taking blood pressure
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Pump sphingomometer until brachial artery is occluded. Lower pressure gradually so artery opens briefly, find diastolic pressure when sound goes away.
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Mean right atrial pressure
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MRAP = CVP
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Total peripheral resistance
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Total resistance of all vessels between left ventricle and right atrium.
Small arteries, arterioles, precapillary sphincters. R = deltaP / Q Peripheral Resistance Unit (PRU) = mmHg/mL/sec |
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Systemic circulation model
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CO = (MAP–MRAP) / TPR
If MRAP = 0, CO = MAP/TPR MAP = CO * TPR = (HR * SV) * TPR |
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Pulmonary circulation model
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CO = (MPAP – MLAP) / Total pulmonary resistance
Pattern of TPR and compliance determines dynamic changes in blood pressure (time constant) |
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Arterial system characteristics
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No resistance
Low compliance High pressure (MAP) Conduit vessels little of total blood volume Afterload determined by compliance |
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Venous system characteristics
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No resistance
High compliance Low pressure (CVP) CVP = MRAP Much of total blood volume Preload – filling pressure of heart |
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Heart valves
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AV – Mitral (bicuspid) on left and tricuspid on right
Semilunar – Aortic and pulmonic |
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Sequence of electrical excitation and contraction
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SA –> RA –> interatrial tracts –> LA –> AV node –> Bundle of His –> Septum –> Purkinje Fibers –> Ventricle
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Primer Pump
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Atria contracts to fully fill ventricles
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When do AV valves open?
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Open passively when proximal (atrial) pressure exceeds distal (ventricular) pressure
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Papillary muscles
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Attached to AV valves via chordae tendinae.
Contract when ventricle contracts to keep AV valves from everting. |
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Eddy currents
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When AV valve is open, form behind valve leaflets as blood enters larger compartment.
Keeps leaflets from sticking to ventricular wall – holds valve "poised" |
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EKG
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P – atrial depolarization
QRS – atrial repolarization/ventricular depolarization T – ventricular repolarization |
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Aorta pressure
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Slowly falls until aortic valve opens. Then rises. Begins to fall. Aortic valve closing causes aortic insicuria (recoil) which raises pressure briefly
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Ventricular pressure
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Begins to increase when mitral valve closes. Increases and then decreases especially when aortic valve opens.
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Why are left ventricle and left atrium pressure the same during diastole?
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Mitral valve has very low resistance
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Isovolumic contraction
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Occurs when mitral and aortic valves are both closed – ventricle develops pressure without changing volume until aortic valve opens (when ventricular pressure exceeds aortic pressure).
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Why are ventricular and aortic pressure the same during systole?
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Very low resistance across aortic valve
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Isovolumic relaxation
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Occurs when aortic valve and mitral valve are both closed at the end of systole – change in pressure as ventricle relaxes without a change in volume until mitral valve opens (when atrial pressure exceeds ventricular pressure).
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Aortic incisuria or notch
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Small increase in aortic pressure right after systole caused by closing of aortic valve.
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Ventricular volume changes
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Atrial contraction causes small increase in volume.
During ventricular contraction and while aortic valve is open, contraction causes reduction in ventricular volume by stroke volume. Falls to end–systolic volume when aortic valve closes. Begins to refill when mitral valve opens. |
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Timing of aortic and mitral valve opening.
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Systole occurs when aortic valve is open.
Aortic valve opens after mitral valve closes and closes before mitral valve opens. |
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Heart sounds
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S1 – generated by mitral and tricuspid valve closing
S2 – generated by aortic and pulmonary closing |
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Ejection fraction
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Fraction of blood in heart ejected.
EF = SV/EDV |
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Stroke work
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SW = MAP * SV
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Difference in Wigger's Diagram of right side of heart
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Smaller pressures
Isovolumic contraction and relaxation begin later and end earlier on right side of heart. 1. Mitral valve opens. 2. Tricuspid valve opens. 3. Mitral valve closes 4. Tricuspid valve closes. 5. Pulmonary valve opens. 6. Aortic valve opens. 7. Aortic valve closes. 8. Pulmonary valve closes. |
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Left Ventricular Pressure–Volume Loop
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A – End–Systolic Volume, mitral valve opens
A–B – Early diastolic filling B–C – Late diastolic filling C – EDV, mitral valve closes. Bump = "atrial kick", preload C–D – Isovolumic contraction D – Aortic valve opens, initial afterload D–E – Rapid ejection F – Aortic valve closes F–A – Isovolumic relaxation |
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Preload
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In cell function – weight that stretched muscle prior to contraction.
Left ventricular end–diastolic pressure Determines initial length before contraction and thus strength of subsequent contraction through length–tension relationship |
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Afterload
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Pressure in aorta against which l.v. must eject blood.
Influences velocity with which LV can shorten – large afterload = smaller velocity = smaller SV. |
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Initial afterload
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Diastolic arterial blood pressure – load must work against after contraction begins.
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Cardiac Function Curve
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Stroke volume as a function of preload.
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Layers in vessels
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Tunica intima, media (smooth muscle), and adventitia
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Viscoelastic components
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Collagen and elastin are more present in arteries and provide compliance
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Vascular trees
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Aorta –> Arterioles –> Capillaries (8 um) –> Venules –> Veins
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Macrovessels vs microvessels
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Veins and large arteries are macrovessels, others are microvessels.
Macrovessels are measured in milliunits and contain elastic tissue and fibrous tissue. Compliance and wall tension dominate. Microvessels are measured in microunits and contain smooth muscle. Resistance dominates. All are lined by single cell thick vascular endothelium. |
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Compliance
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Distensibility.
C = deltaV/deltaP Venous side is 20x compliance of arterial side. Compliance curve is curvilinear – stiffness increases with added volume. Aged vessels are stiffer and less compliant. |
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Wall tension
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Determined by viscoelastic components of cell
Law of Laplace: T = P * r Highest in large, pressurized vessels e.g. aorta Lowest in small, low pressure vessels e.g. capillaries |
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Resistance
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Resistance = Pi–Po/Q
R = 8nL/pir^4 |
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Blood volume distribution
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Heart – 7%
Pulmonary circulation – 8% Venous systemic circulation – 64% Venous system acts as reservoir because it is highly compliant, low pressure, and has increased volume distribution. |
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Pulse and Mean Pressure
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Pulse Pressure = Systolic Pressure – Dystolic Pressure
Mean Pressure = CO * TPR = 1/3S + D |
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Blood Pressure Pattern
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Pulse pressure decreases in magnitude away from heart as compliance diminishes pressure.
Reflection of waves/summation can alter pressure waves – e.g. increasing pulse pressure in femoral artery. Largest pressure drop is over site of maximum resistance, small arterioles. In capillaries, increase in total surface area = smaller drop in pressure. |
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Blood Velocity Pattern
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Decrease in blood velocity down vascular tree as surface area increases. After capillaries, velocity increases as total surface area goes down.
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Effect of vessel compliance on blood flow
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Compliant arteries store fraction of blood in systole. Recoil during diastole maintains flow during diastole.
In rigid/low compliance arteries, flow ceases during diastole. |
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Effect of vessel compliance on work
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Continuous rigid – W = PV = 100*100
Intermittent rigid – W = PV = 200*100 Intermittent compliant – W = PV = 100*100 75 mL is stored in artery walls and released constantly during diastole. |
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Decreased compliance with aging
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Compliance = deltaV/deltaP
Curvilinear – increase in pressure stiffens artery Vessels expand more in 20 year old than 60 year old. |
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Factors affecting pulse pressure
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Arterial blood volume
Arterial compliance CO (HR*SV) MAP (CO*TPR) |
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Effect of compliance on MAP
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Compliance does not change MAP (CO*TPR)
Increasing compliance decreases rate at which new MAP arises because more volume stored in aorta and less contributing to flow. |
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Effect of stroke volume on pressure
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Increase in stroke volume increases pulse pressure and MAP (by increasing CO)
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Effect of compliance on pressure
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If compliance is lowered –
systolic pressure increases (none stored in aorta) and diastolic pressure decreases. Leads to increased pulse pressure but no change in MAP. |
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Effect of increasing vascular resistance
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MAP increases, pulse pressure does not change
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Effect of decreasing compliance
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MAP does not change, pulse pressure increases
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Morphology of Smooth Muscle
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Actin and myosin filaments attach to dense bodies in PM and cytoplasm – analogous to Z lines. Cells connected by gap junctions
PM invaginations are concentrated with receptors and ion channels. |
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Mechanisms of Contraction Initiation
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1. Elevation of [Ca2+]i by Ca2+/TRP channels. Ca2+ binds to RyR.
2. Agonist binds to G–protein, producing IP3 and DAG. IP3 binds to IP3R, DAG activates ROC. |
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Sequestering of Ca2+
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Ca2+ taken up by SERCA or PM Ca2+ pump.
NCX can cause influx or efflux of Ca2+ depending on Na+ levels. |
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Calcium sensitivity
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Increased sensitivity – less Ca2+ required for same MLC20–P
Decreased sensitivity – more Ca2+ required for same MLC20–P. |
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Factors influencing MLCK and MLCP
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Excitation–Contraction Coupling
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Activated by changes in potential but does not need action potential.
1) Inhibition of K channels depolarize membrane. 2) Depolarization coupled to voltage–gated Ca2+ channels (L–type) |
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Pharmacomechanical Coupling – Contraction
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Ga –> PLC –> IP3 (IP3R) and DAG (PKC and ROC)
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Pharmacomechanical Coupling – Relaxation
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Ga –> Adenylyl Cyclase –> cAMP –> PKA –| MLCK
Ga –> Guanalyl Cyclase –> cGMP –> PKG –> MLCP |
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Sympathetic system and blood vessels
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Junctional varicosities release NE which bind to alpha–adrinergic receptors on VSM.
Nerve fibers found at adventitia–media border. NE –> alpha1 –> PLC –> IP3 + DAG Nerves are on outer wall but smooth muscle connected by gap junctions |
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Adrinergic receptors
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Alpha 1 – VSM. NE. ContractionBeta – VSM. NE. Relaxation.
Cardiac muscle. NE. Contraction, increase in HR. |
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Effect of sympathetic neurogenic response
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Does not change MAP because skeletal circuit is isolated
Decreases tissue volume due to venous constriction which moves fluid towards heart Decreases blood flow due to arterial constriction |
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Metabolic Vasodilation
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Influenced by metabolites from tissues – includes adenosine, lactic acid, CO2, H+, K+
Exercise –> Increased O2 Consumption –> Increased AV O2 Difference and Increased Blood Flow |
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Myogenic response
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Inherent ability of VSM to respond to passive changes in pressure.
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Myogenic response to stepwise increase in pressure
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Diameter decreases with small of spike of passive response after each step until can no longer constrict.
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Is myogenic response related to endothelium?
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If endothelium removed, active constriction still detected in response to pressure increase – endothelium activation is not related.
Total myogenic response is difference between passive dilation and active constriction. |
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What is myogenic response based on?
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Increase in pressure results in increase in Ca2+ and spike in diameter.
Adding Ca2+ channel blocker showed no Ca2+ increase and no active constriction. Therefore, pressure activates voltage–sensitive Ca2+ channels. |
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Endothelial Modulation of Blood Vessel tone
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Endothelium separates smooth muscle and blood.
Can produce endothelium–derived relaxing factors (EDRFs) and endothelium–derived contracting factors (EDCFs) – balance determines relaxation and constriction. |
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What stimulates endothelial modulation?
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Increase in flow through isolated blood cell –> increase in diameter.
This effect abolished by removing endothelium. Endothelium responds to flow but not pressure. |
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Flow–induced Vasodilation and Metabolic Vasodilation
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Flow–induced vasodilation can be secondary to increased flow caused by metabolic vasodilation in skeletal muscle during exercise.
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Autoregulation
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Ability of organ to maintain constant blood flow in response to changes in perfusion pressure.
At first, flow increases with pressure but then it plateaus – resistance must be increasing because flow is constant and pressure is increasing (vasoconstriction). Flow increases to A but increased resistance knocks it down to B. |
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Forces in autoregulation
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Mediated by myogenic response
Opposed by flow–induced vasodilation. Assisted by metabolic vasoconstriction – washing out of endothelial vasodilation factors by increased flow |
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Cardiac Fast Action Potential
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Occurs in ventricle, atria, bundles.
Phase 0 – Depolarization/rapid upstroke of AP – Na+ current Phase 1 – Partial repolarization – Ito, closed IK1 Phase 2 – Plateau (sustained depolarization) – Ca2+ current, some IK (inward rectifier), closed IK1 Phase 3 – Repolarization – IK1, IK (inward rectifier) Phase 4 – Rest – IK1 |
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Refractory Periods
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Effective refractive period (c–d) – cell will not respond to stimulus
Relative refractory period (d–e) – cell will partially respond to stimulus |
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Slow Action Potential
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Occurs in AV, SA node
Phase 4 – Pacemaker depolarization – IF, ICa, closing of IK. Phase 0 – Depolarization – IF turns off after threshhold. ICa Phase 3 – Repolarization – IK |
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Differences between slow and fast APs
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Fast APs have:
1) More negative resting potential 2) Faster phase 0 upstroke 3) Larger phase 0 amplitude |
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Temporal relationship between AP and contraction
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Depolarization precedes force development
Completion of repolarization coincides with peak force Duration of contraction is roughly equal to duration of AP |
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Resting potential in fast AP
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Maintained by inward rectifier K+ channels
Small positive outward K+ current that drive membrane potential to EK |
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Nernst potentials of Na, Ca, Cl, K
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ECa = 124
ENa = 70 ECl = –37 EK = –97 |
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Chord Conductance Equation
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At rest, gK is 100x gNa so second term drops out
Vm is about Ek, but slightly less negative because small inward Na+ current |
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Effect of external Na+ on membrane potential
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Does not influence resting membrane potential
Increases peak membrane potential – determines amplitude of action potential |
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Effect of removing Na+ on action potential
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Remove INa with TTX
Fast APs convert to slow APs Elimination of phase 0 upstroke |
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Effect of removing Ca2+ on action potential
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Remove ICa with diltiazem
Blocks phase 2 plateau AP shortens |
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Effect of blocking K+ on cation potential
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Block IKr with E–4031
Longer time to repolarize causing prolonged AP with longer phase 2 plateau. |
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Refractory periods
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Early refractory period – subthrehhold response because Na+ channels inactivated
Late refractory period – Na+ channels have re–activated = faster upstroke with larger amplitude |
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Pacemaker depolarization
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Stage 4 of AV/SA nodal action potential
Driven by Ca2+ channels, closing K+ channels after previous action potential, and IF channels |
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IF channels
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Na+ current that is activated slowly at hyperpolarized voltages
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Phase 0 of slow cardiac AP
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Once threshold is reached:
IF is turned off ICa2+ is further activated by depolarization, then inactivated IK+ is slowly activated and peaks at phase 3, causing repolarization |
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Pacemaker activity
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SA node is primary pacemaker – 60 bpm
AV node is secondary pacemaker – 40 bpm Purkinje fibers are also secondary – 20 bpm |
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Purpose of AV node delay
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Slows conduction, allowing allowing atrial contraction to precede ventricular contraction
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What slows AP propagation
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1. Fewer Na+ channels activated (Na+ channel blocked)
2. Fewer Ca2+ channels activated (Ca2+ channel blocked) 3. Threshold is more positive |
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Effect of raising [K+]extracellular
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Depolarizes cell, inactivating Na+ channels
Leads to slower upstroke, reduced amplitude, and reduced duration of AP Prolonged distance between stimulus and phase 0 = slower conduction velocity. |
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Conduction velocity
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Fastest – Purkinje fibers – many Ca2+ and Na+ fibers
Fast – Ventricle and atria – many Ca2+ and Na+ fibers Slow – SA and AV node – no Na+ channels, only Ca2+ channels. |
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Cycle length
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Time between action potentials
As cycle length decreases, duration of AP decreases and heart rate increases |
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ECG
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Recording of electrical activity of heart generated by change in charge outside cell wall. Measures change in voltage over time.
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Impulse conduction
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SA node –> atria –> AV node –> bundle branches –> Purkinje fibers –> ventricles
Slows at AV node. Somewhat slow at atria and ventricle, fast at Purkinje fibers |
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Amplitude at EKG
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1 mV = 10 mm (2 big blocks)
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Duration in EKG
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1 second = 25 mm (5 blocks)
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Rhythm
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Sinus rhythm goes down and to left.
Electricity coming towards lead shows positive deviation |
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Bipolar Frontal Plane leads
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1 – 90 degrees – RA –> LA
2 – 150 degrees RA –> LL 3 – 210 degrees LA –> LL |
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Unipolar Frontal Plane leads
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aVR – center to right arm – 300 degrees
aVL – center to left arm – 60 degrees avF – down to feet – 180 degrees |
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Identifying sinus rhythm
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+ deviation in lead 1
+ deviation in AVF We need two leads because if current is perpendicular to lead 1, lead 1 will not detect it Or can use lead 2 – where P wave tends to be biggest |
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Precordial leads
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Used to assess front to back rhythm
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If not sinus, rhythm can be
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Ectopic atrial – focused somewhere else in atrium
Junctional – Starts at AV node, goes back into atrium |
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Rate
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Normal (60–100)
Bradycardia (< 60) Tachycardia (> 100) |
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Calculating rate
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Rule of 300 – 300/number of large blocks
Normal sinus rhythm is between 3 and 5 blocks (60–100) |
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QRS complex
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>= 3 blocks (120 ms) – wide – supraventricular with branch block or ventricular (no branch bundle)
< 3 blocks – narrow – supraventricular, normal |
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PR intervals
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Describes AV nodal contraction. Should be 3–5 small blocks (120–200 ms).
>5 blocks PR interval = AV block (first degree) |
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QT interval
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Signals abnormal repolarization and lethal arrhythmias, can be amplified by some drugs
Difficult to measure = varies by gender and heart rate Abnormal if QT interval > 1/2 RR interval |
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Effect of Increased Sympathetic Activity
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E/NE bind to beta–adrinergic receptors –> cAMP
Increased Ca2+ current Increased IF current More rapid depolarization and more negative threshold |
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Effect of Increased Parasympathetic Activity
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ACh binds to muscarinic receptors. Gi –| cAMP –>
Decreased Ca2+ current Decreased If current Less rapid depolarization and more positive threshold Increased ACh –> Gs –> Gbeta/gamma –> Increased KAch current More negative maximum diastolic pressure |
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Effect of isoprotenol on Ca2+ currents
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Isoprotenol is a catecholamine. Increases Ca2+ current through cAMP and PKA.
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Arrhythmias
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Any cardiac rhythm other than normal sinus. Classified as conduction abnormalities or altered excitability/automaticity.
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1st degree AV block
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Abnormal prolonging of PR interval
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2nd degree AV block
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Inconsistent conduction of atrial impulse to ventricles – occasional missing QRS wave
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3rd degree AV block
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Absence of AP conduction – P wave is unrelated to QRS wave and is bizarrely shaped. May follow another pacemaker, can be fatal.
Complete block |
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Unidirectional AV block
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Block is in one leg of conduction pathway and only blocks impulses going one way.
May occur if bolcked region was but no longer is refractory Can be deadly – "reentry loop" |
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Bypass conduction/Wolfe–Parkinson–White Syndrome
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In addition to normal pathway, impulses fo through "bypass tract" directly from atria to ventricles
Results in delta wave – shoulder on QRS complex Also called "pre–excitation complex" |
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Changes in sinus rhythm
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Tachycardia – fast HR, short PP interval
Bradycardia – slow HR, long PP interval |
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Premature atrial depolarization
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2nd P wave is early and obscures T wave
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Premature ventricular depolarization
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3rd QRS complex is early and bizarre.
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Early After Depolarization (EAD)
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Triggered new AP that occurs in relative refractory period at end of phase 2 or mid–phase 3
More likely in slow HR than in fast HR. Injury (or Cs to block K+ channels) causes depolarization of cardiac cells to –50 so Na+ channels are deactivated. Thus, EAD runs are due to IK and ICa. During runs, potential never returns to –50 so Na+ channels are never reactivated. |
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Delayed After Depolarizations (DADs)
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Appear at high HR/small cycle length directly following repeated stimulation.
Associated with increased Ca2+ (i.e. by inhibiting Na/K pump) |
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Supraventricular tachycardia
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No P wave because atria is not depolarizing, ventricles are driven by something else.
Rapid onset and cessation. Fainting or dizziness because inadequate ventricle filling time |
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Ventricular tachycardia
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Originates from ectopic focus in ventricles. Repeated bizarre QRS complexes.
Precursor for ventricular fibrillation |
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Atrial fibrillation
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Most common sustained arrhythmia, not life threatening. Shows irregular QRS waves (does not follow normal ventricular pattern) and no P waves.
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Ventricular fibrillation
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Originates from ectopic focus in ventricles. Many re–entry circuits cause electric activity but no work being done. Fainting and sudden death results.
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Long QT syndrome
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Causes fainting and sudden death. Risk factors are genetics, prolonged QT, emotion, startle, exercise, sleep, drugs. Prolonged QT interval leads to ventricular fibrillation and torsades de pointes.
Can be familial or acquired. |
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Familial long QT syndrome
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Caused by mutations in HERG channel. Reduction of IK causes prolonged AP and prolonged QT interval.
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Acquired Long QT Syndrome
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Affects 1–4% of population
Due to pharmaceuticals that inhibit HERG channel, reducing IKr current and prolonging AP and QT interval. Blocking of other currents can also cause prolonged AP – can be LOF of IK or GOF causing impaired inactivation of INa or IK |
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4 Factors that control CO
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Cardiac factors (unrelated to systemic vasculature): Heart rate and myocardial contractility
Coupling factors (couple heart to systemic vasculature): Preload and afterload |
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Ventricular Preload
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Law of LaPlace: Ws = P x r/2h
P = pressure, r = radius, h wall thickness Can be approximated by end–diastolic pressure Increased EDP = stretching of ventricle cells= increase volume and contraction strength Right ventricle EDP = right atrial pressure = central venous pressure because tricuspid valve and veins have little resistance. |
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Frank Starling Experiment
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Elevate right atrial pressure to increase stroke volume (increased preload)
F–S law – output of each beat (stroke volume) adjusts to match input (preload). Allows left heart to match output of right heart. Important because amount of blood returned to heart varies. SV can be increased by a maximum of 50% to match increase in pressure. |
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Sarcomere Length–Tension Relationship – Cardiac vs Skeletal
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Tension does not fall as low as in skeletal muscle. Tension develops faster with length changes.
Passive – force stretches it to less length |
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Explaining Cardiac Sarcomere Length–Tension Relationship
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Accounted for by:
1. Sliding filament theory – small length has double thin filament overlap and large length has too little overlap. 2. Stretch increases chemical affinity of troponin C to Ca2+, leading to greater force development with small length increase 3. More Ca2+ is released from SR = stronger contraction |
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Why does contraction stop at end–systolic pressure?
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This is maximum force ventricle can generate at this volume.
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Effect of preload on SV
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Increasing preload increases SV by increasing end–diastolic volume while end–systolic volume remains the same.
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Cardiac function Curve
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Shows SV increasing as a function of preload. Also known as Starling curve or ventricular function curve.
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Afterload
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Pressure on heart during ejection phase.
Initial afterload is aortic pressure against which aortic valve opens. Defined as left ventricular wall stress Ws = P * r/2h, approximated by LV pressure because parameters change during systole. High afterload decreased shortening velocity, reducing stroke volume. |
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Effect of afterload on Stroke Volume
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Afterload reduces stroke volume by increasing end–systolic volume (based on ESPVR)
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Sympathetic control of cardiac contractility
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NE –> beta 1 receptors –> Gs –> AS –> cAMP –> PKA
1. Phopshorylates Ca2+ channels. Ca2+ influx activates contraction in ventricle. 2. Phosphorylates phospholamban which usually inhibits SERCA. Removes SERCA inhibition, allowing it to pump more Ca2+ into SR more quickly. 3. Phosphorylates troponin I – reduces troponin's affinity for Ca2+, allowing SR to take up Ca2+ more quickly. Large increase in [Ca2+] overwhelms lowered troponin C affinity. |
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Sympathetic–stimulated cardiac AP
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Peak Ca2+ concentration is higher and reached more quickly because of ICa effects.
Decline is faster because of phospholamban and troponin I effects. |
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Effect of increased contractility on force–length and force–velocity
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Greater force and velocity developed with same preload.
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Effect of increased contractility on volume–pressure and CFC
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Slope of ESPVR increases, causing both increase in stroke volume (decrease in end–sytolic volume) and increase in LV pressure.
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Neural control of cardiac output
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Control of SV – Frank Starling Mechanism. But only can increase by about 50%.
Control of HR – Increase 3–fold. Total CO increases 4–5x. |
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Does parasympathetic or sympathetic tone predominat?
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Atropine (ACh blocker) increases HR substantially. Propanalol (NE/beta adrinergic blocker) decreases heart rate only slightly.
Parasympathetic predominates but there is some sympathetic tone. |
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Differences between sympathetic and parasympathetic stimulation
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Vagal stimulation rapidly decreases HR and removal of vagal tone rapidly increases HRSympathetic stimulation slowly increases HR and removal slowly decreases HR.
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Why does parasympathetic predominate?
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Sympathetic and parasympathetic inputs inhibit eachother but ACh inhibits NE release better than NPY (sympathetic) inhibits ACh release.
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Carotid sinus baroreceptors
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Active at high pressures. Afferents inhibit sympathetic control and stimulate vagal control of heart and vessels.
Decreases HR. |
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HR during inspiration and expiration
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HR increases during inspiration and decreases during expiration.
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O2 need during exercise
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VO2 may increase 12 fold
VO2 = deltaAVO2 * CO deltaAVO2 can only increase 3 fold. Thus, CO must increase 4 fold |
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Resistance and cardiac output during exercise
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TPR falls to 1/3 basal level during exercise due to vasodilation.
CO must increase 3–fold to maintain MAP. |
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Cardiac Function Curve and why it does not fully predict CO
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Quantifies effect of preload on SV or CO.
But CO also influences preload because CO becomes preload (EDP) after flowing through systemic vasculature. |
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Factors that determine cardiac factors
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Cardiac factors – heart rate, myocardial contractility
Coupling factors – preload, afterload |
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Measuring preload
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R.V.E.D.P = MRAP = CVP
Because little resistance over tricuspid valve and right heart. Thus, CVP = Preload |
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SIMULDOG Model
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Heart and lungs – Pump oxygenator
Arteries – tall tube (low compliance) Capillaries – pinch valve (resistance) between arteries and veins Veins – short tube (high compliance) |
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Experimental setup for VFC
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Right heart bypass = can control flow/CO.
Change CO and assess effect on preload (CVP) |
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SIMULDOG – Stop the pump
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Without driving force, pressure gradient between arteries and veins dissipates.
Arterial pressure falls and venous pressure rises. |
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Dead Pressure
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Equilibrated pressure, in absence of any flow. Also called mean circulatory filling pressure or mean systemic pressure.
7.5 mmHg |
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SIMULDOG – Restart pump
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Arterial pressure rises and venous pressure falls. Compliance and TPR accounts for this effect.
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Effect of increasing blood volume on dead pressure
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Increases dead pressure
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Experiment – Effect of increasing CO on Pa/Pv
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Arterial pressure rises and CVP falls.
Arteries and veins undergo same change in volume but arteries are less compliant so same change in volume results in larger pressure change. |
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Effect of increasing blood volume on VFC
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Increasing blood volume increases dead pressure
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Effect of increasing venous tone on VFC
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Increasing venous tone (constriction of veins) increase venous pressure. Thus, it increases dead pressure.
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Effect of changing TPR on VFC
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Dead pressure does not change because no flow at dead pressure.
Increased TPR dams more blood in arterial system and lowers CVP, thus decreasing slope of VFC. |
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Operating point – effect of increase in CVP
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1) CFC – increased CVP = increased preload = increased CO
2) VFC – increased CO = decrease in CVP 3) Repeated cycle restores stable operating point. |
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Mechanisms of Pressor Response
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Evoked when baroreceptors sense reduction in MAP.
Increased sympathetic stimulation of heart = increased contractility and heart rate Increased sympathetic and decreased parasympathetic stimulation of VSM = increased TPR, venous tone |
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Example of Pressor Response – Hemorrhage
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Severe decrease in blood pressure
Decrease in dead pressure = reduction in CO Pressor response – increase HR and contractility = increased slope of CFC Increase venous tone = dead pressure goes back up. Constriction of arterioles (increased resistance) causes reduction in slope of VFC. Result – normal CO and normal MAP. |
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Effect of Myocardial Damage
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Decrease in cardiac contractility = depressed CFC.
Reduction in CO and increase in CVP Pressor response: Increased HR and contractility = increased slope of CFC. Less than ideal because damaged heart. Increased venous tone = increase in dead pressure; increased TPR = decrease in slope of VFC. Result – pressor response restores CO and MAP. |
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Effect of exercise
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Exercise –> sympathetic activation –> increased contractility and HR –> increased slope of CFC
Vasodilation –> decreased TPR = increase in slope of VFC Sympathetic activation –> increased venous tone –> increase in dead pressure = increase in VFC Skeletal muscle pump –> increase in dead pressure –> Increase in VFC Result – much higher CO (4–5 fold) and increased CVP. |
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Functions of Vascular Endothelium
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1. Permeability of capillary
2. Synthesis of vasoactive substances 3. Regulation of vascular tone 4. Immune function 5. Synthesis of other factors – coagulants, cytokines, etc |
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Capillaries
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Single layer tubes of endothelial cells. RBCs transported through in single file.
Cytoplasm wraps around cell and attached by junctions. |
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Types of capillaries
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1. Continuous – low permeability. Found in blood brain barrier.
2. Fenestrated – holes in endothelium. Higher permeability. Found in skeletal muscles, intestine. 3. Discontinuous – gaps between endothelial cells. Highest permeability. Found in liver, pancreas, other endocrine organs. |
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Types of intercellular junctions
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1. Tight junctions – claudins and occludins – no solute transfer
2. Adherence junctions – cadherins – some gappage/permeability 3. Gap junctions – connexins – allow solute transfer. |
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Blood vessel wall
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Tunica intima (vascular endothelium)
Tunica media (smooth muscle) Tunia adventitia (adventitial layer) |
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Endothelium–Dependent Vasoactive Substances
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Relaxing Factors – NO, PGI2
Hyperpolarizing Factors – EETs Contracting factors – ET1, TXA2 |
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Nitric Oxide synthesis
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L–Arginine –NO Synthase (O2)–> L–Citrulline + NO
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NOS Isoforms
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endothelial NOS and neuronal NOS – similar to each other
inducible NOS – not present until induced by inflammatory cytokines. 10–fold higher catalytic rate |
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PGI2 Formation
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Arachidonic Acid –COX–> Endoperoxides (PGG2/PGH2) –PGI2 Synthase–> PGI2
PGI2 is predominant prostaglandin produced by endothelial cells. Other cells produce other prostaglandins (PGD2, PGE2, PGF2alpha) PGI2 is predominant in endothelial because PGI2 synthase is predominant enzyme |
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EET formation
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Arachidonic Acid –cp450 epoxygenases–> EET
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Thromboxane formation
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Arachidonic Acid –COX–> Endoperoxides (PGG2/PGH2) –TX Synthase–> TXA2
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ET–1 Formation
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Big ET1 –Endothelium–converting enzyme (ECE)–> ET–1
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VSM Response to EDRFs
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EETs –> K+ channel –> hyperpolarizes membrane –> relaxation
PGI2 –> AC –> cAMP –> PKA –> relaxation NO –> soluble GC –> cGMP –> relaxation Viagra blocks degradation of cGMP. |
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VSM Response to EDCFs
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ET–1 and TXA2 bind to receptors.
Both receptors activate PLC which create IP3 and DAG –> contraction. |
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Contributions of EDRFs and EDCFs (resting and disease state)
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Normally, EDRFs predominate.
In disease state, EDCFs predominate. |
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Vascular endothelium and vessel diameter
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Flowing blood –> shear stress –> mechanosensors –> Ca2+ elevation –> EDRF synthesis
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Measuring Flow–Mediated Dilation
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Identify blood vessel in forearm using ultrasound.
Occlude so vessel and downstream tissue accumulates metabolites and dilates. Release cuff = increase in flow to vasodilated vessels. Measure increase in flow, increase in diameter, time to peak diameter, recovery |
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Endothelial Dysfunction
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Increased VDCFs because upregulation by ROS
Increased vascular tone (effect of thromboxane) Increased platelet aggregation (EDRFs normally inhibit platelet aggregation, thromboxane and other EDCFs stimulate platelet aggregation) Clot formation |
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Baby aspirin
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Inhibits thromboxane synthesis in platelets to decrease platelet aggregation. No effect on endothelial cells.
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Lymphatic System
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Terminal lymphatics –> Afferent collecting lymphatics –> Lymph nodes (cervical, axillary, inguinal, pelvic, abdominal, thoracic) –> Efferent collecting lymphatics –> Thoracic duct (left) or Lymphatic duct (right) –> Subclavian vein
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Where are lymphatic vessels found
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Travel with arteries and veins. Exists everywhere but bone, cartilage, and CNS
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Terminal lymphatics
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Blind–ended tubes with filaments anchoring them into ECM (keeps vessels open with ECF pressure).
Endothelial cells in oak–leaf arrangement. Button–like junctions (like adherent junctions – some transport into cell permitted) |
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Collecting lymphatics
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Endothelium and smooth muscle with valves to prevent backflow.
Attached by zipperlike junctions (like tight junctions) Has lymphagions |
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Lymphangion
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Functional unit of collecting lymphatics
Inside lined by endothelial cells, outside lined by muscle that has both skeletal and smooth characteristic – exhibits tonic and phasic contraction Driving force provided by contraction of lymphagion rather than pressure gradients. |
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Right and left lymphatic duct
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Right lymphatic duct drains right arm, chest, neck, head, and lower left lung
Thoracic duct drains rest of body |
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Composition of Lymph Fluid
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Interstitial fluid
Solutes proteins Fat Cells (lymphocytes, bacteria, etc) |
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Lymphangion contractile cycle
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We can measure end–diastolic diameter and end–systolic diameter of lymphangion.
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Lymph node
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Has capillary circulation with high concentration of protein.
Capillary collects fluid and protein–filled lymph continues down efferent lymphatic vessel. |
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Net capillary movement in lymph nodes
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(Pc + PIi) – (Pi + PIc)
Filtration – Reabsorption |
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If reabsorption > filtration, lymph formation is driven by:
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1. Transient hydrostatic/oncotic forces
2. Suction due to lymphangion contraction 3. External compression (exercise) 4. Varies along length of capillary |
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Primary lymphedema
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1. Milroy – VEGF–R defect2. Merge's – Lymphatic vessel hypoplasia
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Secondary lymphedema
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Trauma, surgery, irradiation, infection, or cancer causes lymphatic obstruction. Proteins accumulate in IF and fluid drawn in until osmotic pressure decreases. IF to keep expanding without increasing osmotic pressure.
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Differences between edema and lymphedema
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Lymphedema involves protein and fluid buildup.
Lymphedema is permanent if untreated. |
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Riva Rocci
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Palpatory method of measuring blood pressure (RR)
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Korotkoff
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Method of taking BP with stethoscope
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Laennec
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Invented stethoscope
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Correlation of blood pressure with gender
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Young women are relatively protected from high blood pressure (estrogen?). Post menopausal women have increased risk.
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Hypertension and age
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Hypertension rises with age in countries with high salt diet. In countries with low salt environment, blood pressure does not increase with age.Migrants have increased blood pressure.
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Optimal blood pressure
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People < 60 – 110/75
People >80 – 140/70 Diastolic must be less than 80 optimally. |
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Blood pressure and stroke mortality
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Stroke mortality increases exponentially with blood pressure.
Older patients have higher increase of stroke mortality at any blood pressure. |
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Feedback gain
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Measures how effective control mechanism is.
Initial change / residual change e.g. if 10 mmHg pressure rise is corrected by 9 mmHg pressor response, feedback is 10 (10/1) Mechanism that brings blood pressure completely back has infinite gain. |
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Feedback gain / Time graph
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Measures feedback gain of different reflex control mechanisms over time.
Mechanisms have no gain at 0 time. Gain increases and then eventually drops off after many days. |
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Baroreceptor reflex
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Baroreceptors in carotid sinus sense pressure.
Signal transmitted along Hering's nerves –> glossopharyngeal n. –> CNS |
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Carotid body
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Senses hypoxia
Inactive at rest because normoxic |
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Medullary control centers
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1. Cardioinhibitory center
2. Vasoconstrictor center 3. Vasodilator center |
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Cardioinhibitory center
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Changes vagal output to heart, which restraints heart rate.
Cutting vagus leads to ventricular fibrillation and death. |
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Vasoconstrictor Center
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Sends imuplses down spine and out sympathetic chain ganglion to innervate heart, arteries, and veins.
In heart – increases heart rate and contractility In peripheral circulation – increases TPR and venous return |
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Vasodilator center
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Present in some animals but not humans
Has own set of nerves that run to periphery and drops BP dramatically, e.g. to play dead In humans, vasodilation occurs by withdrawing sympathetic activity via vasoconstrictor center. |
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Relation between arterial blood pressure and carotid sinus firing
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Carotid sinus fires with maximal sensitivity just below 100 mmHg and does not fire below 50 or above 150 mmHg.
Small changes in pressure around normal blood pressure causes large changes in firing rate. |
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Relation between arterial blood pressure and aortic arch baroreceptors
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Similar to relation between carotid sinus firing and blood pressure expect shifted right by 20 mmHg – only active under extremely high blood pressure.
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Drop in pressure and stressor response
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Drop in pressure sensed by carotid sinus
Sent to NTS in medulla 1. Withdrawal of vagal output to heart –> increase in heart rate 2. Increased sympathetic activation from vasomotor center Heart – increased HR and contractility Vessels – increased TPR and venous return Total effect – raise blood pressure to normal |
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Rise in pressure and depressor response
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Rise in piressure sensed by carotid sinus
Sent to NTS in medulla 1. Stimulation of vagal output to heart –> decrease in heart rate 2. Withdrawal of sympathetic output from vasomotor center Heart – decreased HR and contractility Vessels – decreased TPR and venous return) increased venous compliance) Total effect – depress blood pressure to normal |
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Overriding pressor and depressor response
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Excitatory emotions, stress, cold, heat, pain, earthquakes, war, floods
Sensed by concious mind – decrease vagal output and increase vasomotor sympathetic output. |
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Denervation of carotid sinus baroreceptors in dog
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Normally, dog is at 100 mmHg but varies between 65 and 125 mmHg.
Denervating carotid sinus baroreceptors increases range to 40 to 160 mmHg without change in mean blood pressure. Baroreceptors influence normal variability but don't affect set point. |
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Blocking spinal neuronal outflow to sympathetic ganglion
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Sharp decrease in BP (100 –> 50)
Rescued transiently by injecting NE Total anesthesia removed input from symphatetic varicosities in vascular wall. |
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CNS ischemic response – effect of hemorrhage
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Experiment – artificially increase subarachnoid pressure
Pushes on brain vasculature, reducing inflow of blood to CNS. Simulates hemorrhage. CNS has own BP sensing system – uses it to initiate pressor response to increase arterial pressure. Relief of subarachnoid pressure restores MAP to normal. |
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Brain response to stroke
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Decrease in TPR to drive more blood to brain.
Can cause more bleeding but also profuses non–damaged tissue. |
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Formation of angiotensin II
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Reduction in BV leads to decreased blood flow in renal artery.
Kidney secrets renin, serine protease. Renin cleaves angiotensinogen into angiotensin I. In lung, angiotensin–converting enzyme (ACE) converts angiotensin I to angiotensin II. |
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Effects of angiotensin II
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Vasoconstrictor of blood vessels
Stimulates aldosterone production in adrenal cortex = salt reabsorption Stimulates arginine–vasopressin production in CNS = water reabsorption Stimulates thirst Effect – blood pressure rises. If not present in hemorrhaging dog, dog dies |
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Atrial Natriuretic Peptide
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Extra volume in circulation causes atrial stretch which stimulates atria to produce ANP.
Effects are: Vasodilation of blood vessels Inhibition of aldosterone production in adrenal cortex Acts as diuretic and natriuretic in kidney Suppresses renin release from kidney (ANP and RAS oppose eachother) Effect – blood pressure falls. |
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ADH involvement in hormonal responses
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ADH only responds to drop, not rise, in blood pressure.
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Living with pets
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Soothing emotions decrease sympathetic vasomotor output and increases vagal output.
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What control system has infinite gain?
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Renal blood volume pressure control system – prevents pressure changes ad nauseum and works over long period of time
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Renal function curve without neural or hormonal inputs
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Below 50 mmHg, reabsorption > filtration so 0 volume output.
As P increases, filtration > reabsorption and kidney excretes salt and water. Excretion by kidney decreases blood volume. Results in feedback mechanism (RAS) that increases CO and restores blood pressure. |
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Renal function curve equilibrium point
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Point at which renal output of water and salt balances water and salt intake. Occurs at MAP just below 100 mm Hg.
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How to chronically change blood pressure
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a. Shift renal function curve to right – angiotensin 2, constriction of renal arteries. Volume goes up b/c not filtering and blood pressure rises to new state.
b. Increase salt/volume intake – increases CO and drives blood pressure up. |
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Experiment – infuse dog with 1L saline without short term control
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1. Dramatic increase in CO
2. Arterial pressure rises dramatically (cannot decrease TPR) 3. Blood pressure rises, increasing filtration in kidney to eliminate volume. Venous return, cardiac output, and blood pressure fall to normal. |
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Experiment – administer aldosterone to enhance reabsorption of salt and water beyond filtration
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Cardiovascular system fills with volume. ECF volume increases by 33% and blood volume increases by 20%.
Reflexes – TPR falls but does not compensate for increased CO completely. As pressure increases, kidney filtration increases until it exceeds reabsorption force by aldosterone. Eventually, fluid volume, blood volume, blood pressure, cardiac output drops to normal. TPR increases chronically. Phases – 1) Cardiac output increases. 2) TPR elevates. |
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Presentation of patients with long history of hypertension
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Patients with long history of salt and volume dependent high BP with normal CO have severely elevated TPR.
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Clinical analogies of administering aldosterone
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Salt–sensitive essential hypertension
Primary hyperaldosteronism caused by adrenal tumors/hyperplasia |
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How does increased cardiac output become increased total peripheral resistance?
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Autoregulation – tissues don't like to be overprofused by heart. Regulates own flow by increasing resistance.
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Relationship between urine/dietary Na+ and Plasma Renin Activity
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Plasma renin activity decreases with higher urine or dietary Na+.
Plasma renin activity has maximum sensitivity at small sodium level because ancestral diets had low salt. Western diets are high in salt. |
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Effect of angiontensin II levels on renal function curve
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Shifts renal function curve right because at same pressure, lower sodium output in presence of angiotensin II.
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How is blood pressure maintained with increases or decreases in salt intake
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If raise salt intake 10x –
Renin and angiotensin II go down. Shifts RFC left so blood pressure doesn't change. If lower salt intake 10x – Renin and angiotensin II go up. Shifts RFC right so blood pressure doesn't change. Aging causes defects in RAS and renal function so blood pressure does rise with increased sodium intake. |
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Effect of renal artery stenosis
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Stenosis is partial blockage of renal artery, decreasing blood flow into kidney. Mimic by clipping renal artery.
– Renin secretion goes up – Aldosterone goes up – Blood pressure goes up – Pressure in renal artery returns to normal – but inappropriate amount of renin for systemic circulation/high blood pressure. Treat by removing clip or removing stenosis. When renal blood flow restored, renin secretion declines and blood pressure returns to normal. |
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Renal function curve for non–salt–sensitive hypertension
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Non–salt–sensitive phenotype – increasing or decreasing salt does not change blood pressure (close to infinite slope)
– More sensitive to ACE inhibitors, Ca2+ channel blockers, beta blockers, etc |
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Renal function curve for salt–sensitive hypertension
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Salt–sensitive phenotype – decreasing salt intake decreases blood pressure.
– More sensitive to diuretics because have extra volume |
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HTN and cognitive impairment
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HTN is linked to cognitive impairment
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Vessels and functions
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Arterioles – resistance vessels
Capillaries – exchange vessels Venules – capacitance vessels with some resistance |
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Ratio of pre– to post–capillary resistance
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4:1
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Importance of sympathetic tone of arterioles
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Prevents excess flow from entering and damaging capillary bed
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Non–nutritive flow
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Flow through shunts directly from arterioles to venules
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Metaarterioles
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Vessels with characteristics of both arterioles and venules – acts as a conduit under neural control.
Blood in metaarterioles can enter capillaries – regulated by precapillary sphincters in mesenteric circulation only. |
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Capillary pressure formula
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Since pre:post resistance is 4:1:
Pc = 100 * 1/5 + 5 * 4/5 = 24 mmHg |
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Colloid osmotic pressure
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Due to dissolved proteins
Albumin (produced by liver) is at 5.0g/100L and exerts 20 mmHg oncotic pressure Globulin and fibrinogens are heavier and at lower concentration – exert additional 6 mmHg oncotic pressure Total 26 mmHg oncotic pressure |
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Starling Equation of Microcirculation
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Kf is a capillary hydrostatic permeability pressure. Higher in leaky organs such as liver.
First term is filtration, second term is absorption |
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Tissue pressure (Pt)
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Tissue pressure is usually –1 to –3 mmHg – tends to pull fluid out of capillary.
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Bee sting
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PIif goes up, PIp goes down.
Increases permeability of vascular endothelium. NFM increases. Fluid follows protein into interstitial fluid, causing swelling. |
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Renal failure
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Increased venous pressure
4/5 venous pressure is transmitted to capillary Pc, so Pc increases. NFM increases Fluid accumulates and moves to legs causing lower extremity edema. |
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Liver disease, nephrotic syndrome, and starvation
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Liver disease – albumin not made
Nephrotic syndrome – kidney leaky to albumin so excreted in urine. Starvation – low dietary protein In all cases, PIp decreases causing NFM to increase. Edema in peritoneal cavity = ascites |
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Capillary and oncotic pressures in lungs
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Low pressure circulation from right heart because lung is low resistance to allow large CO to pass = Lower Pc
Lung capillary bed is leaky to proteins = Higher PIif PIp is the same Pt is same as interthoracic pressure – Lower Pt Overall, NFM is lower than average. Can be measured in water vapor on breath. |
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Left Ventricular Failure
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LV can't pump enough blood away so Pc goes up in lung capillaries.
NFM increases dramatically. Fluid cannot be exhaled so builds up in lungs, leading to crackles and then drowning. Treat by augmenting LV function or lowering venous return with diuretic to lower cardiac output. |
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Capillary and oncotic pressures in kidneys
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Low renal vascular resistance – high Pc
Kidney impermeable to protein – low PIif Fast flow through glomerulus and increase in concentration of protein in capillary – high PIp NFM is very high – a lot of filtration |
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Wall tension
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T = P x rCapillary has much smaller wall tension than aorta because of small radius. Thus, capillaries are more stable.
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Wall stress
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WS = P x r/2h
Thickness of aorta reduces wall stress to 10x level of capillary. |
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Ameurysm
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Weakening of aorta wall leads to enlargement and increase in radius, leading to an increase in wall tension. Cycle continues until aorta breaks.
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Difference in blood flow of tissues
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Brain, Liver, Kidney, and Muscle have most flow
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Difference in organ weight
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Muscle and skin are heavy organs
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Difference in normalized blood flow between organs
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Kidney has most flow/unit volume because low afferent resistance allowing high filtration pressure.
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Difference in blood flow per weight between organs
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Heart, liver, and brain are also highly vascularized. Skin and bone are not.
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Difference in AV O2 Difference between organs
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Heart extracts a lot of O2, kidney extracts very little because has so much blood flow
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Kidney blood flow
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Huge resting blood flow but limited capacity to further increase flow and small AV O2 difference.
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Left ventricular wall vasculature
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3000–5000 capillaries per mm^2. 900 perfused at rest.
Intercapillary distance is 18 um, the size of cardiac muscle fiber |
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Effect of systole on right coronary artery flow
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Peak flow occurs during systole with dynamics similar to aortic pressure
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Effect of systole on left coronary artery flow
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Flow is lower during systole and peaks during diastole (80% of flow in diastole)
When LV contracts, wall is thicker (distance increases) and vessels shrink (resistance increases) so flow drops. |
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Influence of heart rate rise on coronary perfusion
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Diastole (time for maximum flow) shortens much more than systole (time for maximum work).
Diastole shortens until 140 bpm HR. |
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Factors that determine coronary blood flow
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Metabolites (adenosine), beta receptors, myogenic mechanisms increase coronary blood flow
Alpha receptors, vagal tone, systolic compression, and myogenic mechanisms decrease coronary blood flow |
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Effect of oxygen content of perfusate on coronary blood flow
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Below 50% oxygen tension, coronary arteries sense low O2 and dilate to increase flow.
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Effect of oxygen consumption on coronary flow
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Increasing work increases oxygen consumption, which increases coronary flow.
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Metabolic mechanism for changing coronary flow
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Increase in work increases vasodilator production, reducing arteriolar tone and increasing flow in capillary network.
Vasodilators include K+, pyrophosphate, CO2, lactate, and acid |
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Autoregulation of blood flow
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Sustained increase in arteriolar pressure leads to increase in blood flow that is autoregulated to close to baseline.
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Effect of autoregulation on perfusion pressure–coronary flow relationship
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Autoregulation flattens out curve so flow is uncoupled to pressure.
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Active hyperemia
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Increase in work leads to increased flow
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Reactive hyperemia
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Anoxia –> reduced flow.
Relief of anoxia leads to overshoot in increase of flow. Flow is then reduced back to normal. |
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Sequence of arterioles
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Conduit a. –> Feeder a. –> 1A arteriole –> 2A arteriole –> 3A arteriole –> capillaries
3A arterioles are site of highest resistance |
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Upstream vasodilation mechanisms
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1) Metabolic vasodilation
2) Myogenic mechanism 3) Flow–induced vasodilation |
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Myogenic mechanism
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Increased downstream flow and lower downstream resistance causes decrease in 1A and 2A pressure.
Decrease in pressure causes increase in diameter. Does not require endothelium. |
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Flow–induced vasodilation
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Mechanoreceptors sense increase in LONGITUDINAL pressure/flow. Communicate with focal adhesion kinase through actin stress fibers. Phosphorylates eNOS, producing NO and causing dilation.
Endothelial dependent |
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Factors determining coronary tone
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Vasodilator metabolites
Sympathetic constriction increases basal coronary tone |
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Treatments for blocked coronary arteries
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Bypass, stents.
Gene therapy, stem cells, grafts are developing solutions. |
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Muscle blood flow
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21% blood flow
45% organ weight not well vascularized |
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Brain blood flow
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14% blood flow
Small organ weight Highly vascularized |
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Skin blood flow
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7.5% blood flow
7.5% organ weight Not highly vascularized |
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Changes in blood flow with exercise
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Skeletal muscle increases dramatically
Skin increases dramatically when sweating without work being done Brain does not increase Heart increases because increasing CO GI/Liver decreases |
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Skeletal muscle pump
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Muscle contraction augments venous return 4–fold
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Main organ of TPR
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45% of TPR comes from muscle so dilation of muscle bed drops TPR dramatically.
Sympathetic tone (NE –> alpha adrinergic) to muscle. Opposed by beta receptors. Some species also have ACh input from vasodilator center (playing dead) |
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Effect of exercise on resistance
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Metabolic dilation exceeds increase in sympathetic input, so overall response is dilation.
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How is decrease in resistance carried to upstream vessels?
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1. Metabolic vasodilation
2. Myogenic mechanism 3. Flow–induced vasodilation |
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Effect of prolonged leg exercise on forearm blood flow
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Delay between increase in blood pressure and increase in forearm blood flow.
Exercise increases temperature of venous blood which is brought to body core. Increase in temperature sensed by core body receptors and cause increase of flow to forearm (delay). |
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Arrangement of blood vessels in apical skin
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Venous plexus connects arteries to vein collecting blood from capillary loops.
Venous plexus connected to artery by sympathetically controlled shunts – activated by NE to alpha–adrinergic receptors. Withdrawal of sympathetic input causes filling of venous plexus. |
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Effect of heat on hand and forearm blood flow
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Increase in core temperature causes hand blood flow to go up immediately and forearm blood flow to go up in two phases.
A. Brain withdraws sympathetic input and venous plexi fill with blood – accounts for hand and first stage in forearm. B. Active neurally mediated vasodilation due to sympathetic cholinergic tone to forearm but not hand. Associated with onset of sweating. |
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Sympathetic nerve block on forearm blood flow
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Alpha–adrinergic block – first phase of vasodilation occurs but second phase abolished.
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Second phase of increase in forearm blood flow
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Sympathetic cholinergic nerves go to forearm but not hand.
1. ACh receptors on sweat glands stimulated. 2. Kallikrein (bradykinin–forming enzyme) activated. 3. Bradykinin produced 4. Bradykinin binds to bradykinin receptors, causing dilation. |
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Sweating and exercise capacity
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Sweating –(bradykinin)–> vasodilation –> more CO perfuses skin and less to exercise –> impaired athletic performance
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Effect of body heat on different tissues
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Vasodilation of forearm and skin vessels (withdrawal of sympathetic alpha 1, activation of sympathetic cholinergic)
Decline in splanchnic, renal, muscle blood flow because of increased sympathetic drive. |
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Effect of body heat on CO
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CO increases – SV goes up slightly because of sympathetic stimulation but HR goes up dramatically.
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Effect of body heat on MAP
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MAP falls because diastolic blood pressure falls as TPR falls due to skin and muscle dilation (overcomes increase in resistance from other beds)
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Effect of body heat on central blood volume
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Central blood volume initially goes down because blood is pumped into skin. Later goes up because blood is pushed from splanchnic, renal, muscle.
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How is heat lost
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If skin temp > external temp – lose heat by radiation and conduction
If external temp > skin temp – gain heat by radiation and conduction. Can only lose heat by evaporation (stress) Things that prevent stress (humidity, antiperspirants) prevent heat loss |
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Core temperatures
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Normal – 96–100
Medical emergency – 106 |
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Heat related deaths
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Men more at risk than women.
Mortality is increasing overall. Causes of death – mostly chronic ischemic heart disease |
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Why are elderly more at risk for cardiac events in heat?
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Max heart rate declines with age so decreased ability to withstand heat
Loss of HR related to attenuated flow response to ACh. Increased sympathetic activity + HR –> arrhythmia –> death |
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Circulation of Brain
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Cerebbral circulation can autoregulate blood flow over large pressure range using strong myogenic response.
Myogenic response is stronger in brainstem than cortex so brainstem function is protected first. Brain is most sensitive in body to H+ and CO2 (NO as mediator) and also vasodilates with K+ and adenosine Brain has limited ability to respond to sympathetic or hormonal stimulation |
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Danger of vasodilator in chronic hypertension patient
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Hypertension shifts pressure–flow curve to the right – maintain flow over higher pressure.
Vasodilator can move patient off edge of P–Flow curve causing sudden drop in flow and cerebral ischemia. Drop in pressure activates pressor response. Vessels dilate but may be still unable to maintain flow because ability to dilate compromised due to thickened vessel walls. |
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Coronary arteries
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Right coronary artery
Left coronary artery splits into LAD and circumflex artery |
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Autoregulation of coronary artery stenosis
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Vasodilation distal to obstruction reduces velocity and maintains flow
Occurs above 50% stenosis |
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Steps to angina, MI, death
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1) Ischemia – supply–demand mismatch
2) Diastolic dysfunction – impaired filling of left ventricle 3) Regional systolic dysfunction – hypoxic area contracts less. 4) Electrical transit abnormalities – picked up in EKG 5) Symptoms |
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Hibernation or repetitive stunning
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Decrease in wall movement in ischemic areas
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Imaging impaired conduits
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Even 80–90% stenosis (unstable angina) in one vessel can show as normal flow because of compensatory mechanisms
During stress, area of hypoxia increases flow less than healthy areas of heart |
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Ischemic but viable myocardia
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Defect at stress but not at rest
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Fixed defect
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Detected at stress and rest. Can be due to previous MI or to hibernating myocardia
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Chance of MI ny buclear study result
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Normal nuclear study – <1% chance of MI, same as population risk
Abnormal nuclear study – >7% change of MI |
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Hypertrophic cardiomyopathy patients
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Increase in O2 demand because of thick walls leads to ischemia or infarct.
Familial form is found in younger individuals. Ischemia is induced by exercise. ECG shows ST elevation –> cardiac arrest –> ventricular tachycardia |
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Conducting stress test in immobile patients
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Adenosine
4 subtypes – A2A = vasodilation A1 = conduction abnormalities A2B/A3 = bronchoconstriction Ensure patient does not have asthma or heart lbock if administering adenosine. Otherwise, administer A2A agonist. |
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Coronary Flow Reserve
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Stress Flow/Rest Flow
Isolated, significant stenosis – CFC = 1.0 Isolated, nonsignificant stenosis – CFC = 3.4 – no intervention needed Diffuse arterosclerosis without stenosis – CFC = 1.4 Ischemic – aggressive medical therapy or bypass needed |
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Which area in heart is most likely to be hypoxic?
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Endocardium because of intramural pressure from endocardium to epicardium.
If "bridging" vessel that goes into myocardium, that area will be hypoxic. |
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Ejection fraction and mortality
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Drop in ejection fraction below 45% leads to large increase in mortality. Thus, changes in EF below 45% are significant for decreasing mortality
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Ejection fraction
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EF = (EDV–ESV)/EDV = SV/EDV
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Measuring volumes in heart
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MUGA – Tag RBCs and observe travel through vessels and chambers.
Measure SV, EF, septal wall defects |
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Left Ventricle Time–Activity curve
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Measures changes in volume of left ventricle over time and can be used to calculate SV and EF.
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Hypertrophic cardiomyopathy time–activity curve
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Delayed diastolic filling phase – because thick ventricles do not allow blood to fill.
Correct with drug verapamil. |
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Metabolic mechanism to cope with hypoxia
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Stenosis –> Decrease in flow –> Decrease in O2 supply –> Switch to anaerobic glycolysis from FA metabolism –> Programmed cell survival
Palmitate produces 129 ATP and glycolysis only produces 36 ATP – so area becomes dormant. |
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Visualizing metabolic changes
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Label with fluorodeoxyglucose (FDG), a metabolic agent for glycolysis.
Areas that do not appear with flow agent but do appear with FDG are dormant. Patients with these areas should undergo revascularization and not heart transplant. |
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Identifying dormant myocardium
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Stain simultaneously with flow agent and FDG at peak exercise.
Area that is ischemic at rest (does not stain with FDG) becomes dormant during exercise because of increased O2 (stains with FDG). |
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Molecular imaging of vulnerable plaques
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Assess plaque composition by labeling structural elements or pathological features of plaque.
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Cardiac index
|
Used to normalize CO to body surface area.
CI = CO/BSA |
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Causes of dilated cardiomyopathy
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Viral, bacteria, EtOH, drugs, deposition diseases (hemachromatosis, amyloidosis), inflammatory conditions
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Ejection Fraction
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EF = EDV–ESV/EDV = SV/EDV
Can measure precisely with MRIs |
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Typical findings of heart pressure
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Dyspnea (shortness of breath)
Orthopnea (must prop up to breathe) Paroxysmal nocturnal dyspnea (waking up with shortness of breath) Edema Fatigue Limited Capacity for Exertion |
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NYHA Functional Score
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Used to score capacity for exertion.
Class I – no CHF symptoms Class II – symptoms on greater than normal activity but can walk several blocks or 1 flight of stairs Class III – symptoms on less than normal activity. SOB with less than one block or flight of stairs Class IV – Symptoms at rest. Fatigue 24/7 and easy SOB. |
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Orthopnea
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When laying flat, venous return/preload is enhanced. If heart cannot handle preload, elevating head reduces rate of flow
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CHF Exam Findings
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Low blood pressure
Pulses alterans Fluid retention |
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Pulses alterans
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Pulses alternate between strong and weak because of decreased CO
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Dependent edema
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Dependent on gravity, settles where gravity pushes it.
"Pitting" – remains impressed after pressed. |
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Why is fluid retention a finding of CHD?
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Increased jugular venous pressure/high venous pressure = high hydrostatic pressure.
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CFC and VFC for CHF
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CFC has lower slope because of reduction in contractility.
VFC moves right because of higher CVP and compensation mechanisms related to fluid retention. Equilibrium volume is now in range of pulmonary congestion. |
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CHF in P–V Loop
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Elevated LVEDP
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How to improve cardiac output
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Increase HR
Decrease afterload (to increase SV) Increase contractality – glycosides (digitalis) or catecholamines Investigator – Ca2+ sensitizor, myosin activator, NO donor |
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Elevating HR to increase CO
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Highest increase in CO at medium increases in HR – further increases lower stroke volume
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Exercise and CFC and VFC
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VFC increases in slope (decreased TPR)
VFC shifts right (increased venous tone and muscle pump) CFC increases in slope (increased heart rate and contractility) |
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Effect of afterload on SV (and CO)
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Decreasing afterload causes aortic valve to open sooner and close later so heart has more time to pump blood higher SV = higher CO.
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Effect of catecholamines and Ca2+ on contractility
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NE produces cAMP which produces PKA.
1. Phosphorylates and opens Ca2+ channels. 2. Phosphorylates phospholamban to activate SERCA. 3. Phosphorylate troponin I to release Ca2+ from troponin C. |
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Effect of PKA on contraction
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PKA = peak force is higher because of increase in Ca2+. Relaxation is faster – SERCA and troponin I effects.
Isoproterenol, dobutamine mimics effects of NE. Increase in Ca2+ increases chances of arrythmias. |
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Effect of digitalis on contractility (and CO)
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Blocks Na/K ATPase so [Na+]i goes up.
NCX brings Ca2+ in, resulting in an increase in contractility |
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Ca2+ sensitizer – effect on impulse
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Calcium sensitizers do not increase calcium
Same rate of tension rise but longer systole and force development (as oppose to NE agonists – shorter systole). |
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Calcium sensitizers and PV Loop
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Also lowers LVEDP (recall in CHF + exercise, LVEDP is raised) and increases stroke volume.
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Myosin activators
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Strengthen actin–myosin interaction
Allows more shortening and longer length of contraction (not long enough for tetany) Does not increase [Ca2]i (as with PKA) |
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LV Dysfunction
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Dilated left ventricle
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Pulse wave velocity
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Pulse wave velocity is 10x blood velocity. Travels in artery walls
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Pressure wave in femoral artery
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Pulse pressure increases slightly and mean arterial pressure decreases slightly.
Increased pulse pressure is due to reflected pulse waves (RPW) at bifurcations. Adds to forward wave – "distal pulse amplification" |
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Effect of stiffness on waveform
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Stiffness increases velocity of blood so reflected pulse arrives at aorta rapidly.
Reflected wave augments forward travelling wave and abolishes reflected wave. Stiffness increases pulse pressure. Increases systolic and lowers diastolic pressure. |
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Measuring distal pulse amplification
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Augmentation index
AI = Augmented Pressure/PP * 100 |
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Consequences of distal pulse amplification
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1. Increased LV afterload (aortic systolic pressure)
2. Decreased coronary artery perfusion, since peak coronary artery flow occurs in diastole. |
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Relationship between age and pulse wave velocity
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Pulse wave velocity rises 2 fold as age increases. Indicates a decrease in compliance
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Relationship between age and pulse pressure
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Pulse pressure increases because stiff arteries –> distal pulse amplification
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Morphology of aged and stiff arteries
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Abnormal, diarrayed endothelium
Increased collagen, fibronectin Disarrayed elastin Vessel wall thickening Gradual increase in artery lumen diameter Inflammation Hyperplasia of VSM Decreased NO bioavailability |
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Carotid Intima–Media Thickness
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Measure change in vessel morphology. Measured with ultrasound.
Related to atherosclerosis, stroke, heart failure – increase in 0.1 mm –> 10–15% increase in MI, 13–18% increase in stroke Aged have increased intima–media thickness – operate on "edge of disease" |
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Age–induced changes in endothelial function
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1. Reduced eNOS expression and action
2. Production of endogenous eNOS inhibitors. 3. Accelerated NO degradation 4. Increased PDE activity, degrades cGMP (inhibits NO action) 5. Increased production of ROS, inflammation |
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Results of endothelial dysfunction
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Cerebral hypoperfusion –> cognitive dysfunction, Alzheimers
Coronary artery insufficiency Erectile dysfunction |
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Result of inhibiting endothelial NO production
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Inhibit in vitro with L–NAME
Results in increased pulse wave velocity (stiffer arteries) |
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Effect of phenylephrine on pulse wave velocity
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Phenylephrine (PE), alpha 1 ligand, also increases pulse wave velocity.
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Effect of nitroprusside on pulse
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Nitroprusside, NO donor, decreases pulse pressure and increases compliance (lowers AI)
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Cardiac Aging Features
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Increase in LV wall thickness (more connective tissue, less myocytes)
Decrease in early diastolic filling (impaired LV relaxation) – compensatory increase in atrial contribution to LV filling Decreased cardiorespiratory reserve and ability to increase CO and VO2max. Impaired ability to increase HR. Decreased efficacy of sympathetic drive Increased likelihood of arrythmia |
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Effect of aging on Diastolic Length and Contraction Amplitude at high stimulation frequency
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Length of diastole and contraction amplitude goes down at high stimulation frequency. Unable to relax or increase contraction strength
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SERCA in aged myocytes
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Less active, causing longer contraction and longer maintenance of [Ca2+]i. May account for impaired ventricular relaxation and slow diastolic filling.
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Aged diastole
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During aged diastole, early ventricular filling is diminished. Larger atrial kick compensates to fill ventricle.
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Aged sympathetic nervous system
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No deficit in catecholamine synthesis but diminished response to NE (diminished contractility and HR). NE is less effective at increasing Ca2+ current, increasing [Ca2]i, and producing twitches.
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Increasing CO of aged heart
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Since cannot increase contractility and HR does not increase much (2 fold rather than 4 fold), increase SV by increasing EDV instead of reducing ESV.
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Contractility Index and Aged Heart
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Contractility Index = Systolic BP/ESV
Rest CI is constant throughout life. Exercising CI decreases with age – significantly declined by age 40. |
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Aging and changing EF
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Because must increase EDV to increase SV, cannot increase EF very much.
EF = SV/EDV – both SV and EDV go up |
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Aging and maximum CO and VO2max
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CO and VO2max are linearly related to work (energy expenditure). Both decline with age because...
Cannot increase HR Decreased sympathetic function and contractility Increased afterload (stiff arteries, diminished NO and endothelial function) Diminished ability of tissue to utilize O2 |
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Aging and aerobic conditioning
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Aerobic conditioning protects endothelial function, arterial stiffness, CO (increases SV and decreases afterload).
Aerobic conditioning cannot change maximum HR. |
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