Week 1 - Hassid Flashcards
1
Q
What does cardiac autonomic innervation look like?
A
- SYM, PARA efferent nerves emanate from different areas of the medulla:
1) Cardioacceleratory center determines level of SYM drive; transmitted via the SYM cardiac N -> influences SA, AV, ventricular cells
2) Cardioinhibitory center determines parasympathetic drive; PARA via vagus N -> influences SA, AV, NOT ventricular cells - NOTE: NE and E elicit vasoconstriction in coronary vessels, but vasodilation may be observed due to increased rate of myocardial metabolism induced by these drugs
2
Q
What are the stages shown here?
A
- Typical cardiac action potential
- Phase 4: resting phase -> in typical ventricular cell, resting potential set around -85 mV
- Phase 0: action potential begins; very rapid rise in potential so (-) potential actually reversed to ~ +20
- Phase 1: short-lived repolarization
- Phase 2: prolonged plateau
- Phase 3: Cells repolarize to resting phase, and the cycle begins all over again
3
Q
Explain this diagram.
A
- Principal ACT channel in resting phase is Kir2.1 (aka K1), assisted by two other K channels (IKATP and IKAch) -> set resting potential at close to K reversal potential, i.e. about -85 mV
- Phase 0 induced by rapid Na channel ACT (inward current downward yellow tracing); K channel INACT
- Phase 0 transient, followed by Ito channel ACT (transient outward K channel; all K channels green), slightly repolarizing cell mem in phase 1
- Phase 2: inward Ca current (red) balanced by 3 outward K currents (Ikur, Ikr and Iks). REACT of K1 at end of phase 2, leading into Phase 3
- W/REACT of 2 o/K channels (IKATP and IKAch) induces repolarization of cells -> ALWAYS acting together, and mostly during Phase 4
- NOTE: Na channels need to have potential close to -85 mV to “reset” for the next cardiac cycle
4
Q
Describe the pathway of an action potential via the ventricular muscle ion channels.
A
- Action potential causes depolarization, explosive opening of fast Na channels -> tremendous INC in voltage due to entry of Na (positive ion) into cells; Na opens & closes immediately
- Transient outward potassium current (ITO) causes small notch of repolarization
- Smaller, slow Ca channel opens to maintain gradient
- Ultra rapid, rapid, then slow K open to balance things out (K leaving cells, Ca coming in), maintain stable cell membrane potential
- As Ca channels start to close, K1 kicks in and re-polarizes cell (w/aid of ATP and Ach in some cases)
- NOTE: 2 categories of K channels -> those active in hyperpolarized cells (Ik1, IkATP, IkAch) and those active in depolarized cells (Ikur, Ikr, Iks)
5
Q
How does the voltage-gated NA channel work?
A
- Two gates activated at different voltages:
1. V gate: opens at mem potentials more (+) than -40 mV
2. Inactivation gate: opens at mem potentials more negative than -65 mV - At rest, V (voltage) gate closed bc cell mem at the resting level (-85 mV), but inactivation gate open
- When cells reach threshold potential, V gate opens rapidly before inactivation gate has time to close (flicker of opening) -> Na influx + rapid further depolarization of cells in feed forward manner (both gates open + more open as mem voltage more +)
- Milliseconds later, inactivation gate swings shut bc of positive membrane potential (prevents multiple action potentials from occurring; refractory to more activation bc inactivation gate closed)
- When cells repolarize in phase 3, V gate closes & inactivation gate opens
- In SA cells (pacemaker cells) -> fast Na channel permanently inactivated bc of more (+) resting mem potential in these cells; keeps INACT gate closed
6
Q
Wha are the differences b/t the action potentials in SA node cells and those in ventricular myocytes?
A
- Max (-) mem potential, aka max (-) diastolic potential in SA node cells -65 mV, as compared to -85 mV in ventricular myocytes
- Resting mem potential in SA node cells unstable bc funny Na current activated by NEGATIVE mem potential, unlike fast Na current which is activated by POSITIVE membrane potential
- Few fast Na channels active in SA cells bc more + mem potential (-65 mV) suppresses fast Na channel “resetting” event that needs mem potential more negative (-85 mV) than the cells provide
- No plateau phase for SA cell action potential, but in ventricular myocytes, K channel activity DEC during phase 2, but not zero, due to activation of K channels w/low activity, balancing inward Ca current -> plateau phase in ventricular myocytes
- Rate of action potential in SA much slower than in ventricular cells bc Ca channels much slower than fast Na channels
7
Q
Discuss the ion fluxes into and out of pacemaker cells.
A
- Ca channels that open late in pacemaker potential are T-type channels that open and close rapidly
- At threshold, L-type Ca channels open
- Slope of action potential less steep in these cells than in ventricular cells bc Ca channels slower in conducting current than fast Na channels that open in ventricular cells
- At peak action potential, Ca channels begin to close and voltage-gated K channels begin to open
8
Q
What are refractory periods?
A
- Absolute refractory period when no stimulus, regardless of strength, can induce action potential, and is dependent on refractory fast Na channels
- Effective refractory period: no stimulus generated by surrounding cells can elicit action potential
- Relative refractory period: very strong stimulus can elicit action potential weaker than normal action potential (bc some, but NOT ALL of the Na channels have reset; duration will be less)
- Supranormal period: weaker than normal stimulus can elicit action potential -> depends on refractory K channels that have not fully activated, and are unable to clamp resting voltage in face of stimulus, i.e., Na channels have completely reset, but the K ones have not (increased sensitivity)
9
Q
Why is the refractory period important?
A
- Without refractory period, you would have serious arrhythmias, i.e., it is critical to rhytmic and effective contraction
- Has to be refractory period to allow for ventricular filling for next cycle
10
Q
Describe the different cardiac conduction rates.
A
- SA node: highest rate of spontaneous discharge, and normally sets rate of the heartbeat (continually suppressing all other pacemakers via refraction
-
AV node: next lower discharge rate, and can be pacemaker in case of ineffective SA pacemaker
1. Slower to allow time for ventricular filling -
Bundle of His/Purkinje: can assume pacemaker role in event of complete heartblock, i.e., no conduction across AV node, albeit at rates that are not adequate in the long term
1. Spontaneous activity in ventricular cells induces arrhythmias - PARA tone slows down heart, making resting HR around 60-80 instead of 100-120
11
Q
What are the effects of PARA and SYM activity in the heart?
A
-
SYM: dependent on inactivation of K channels, and activation of Ca channels
1. Increases HR
2. Increases conduction velocity (esp. in AV node)
3. Decreases (make more -) the threshold of Ca channels; increases excitability of latent pacemakers and other cells -
PARA: dependent on activation of K channels, and inactivation of Ca channels
1. Decreases HR
2. Decreases conduction velocity (esp. in AV node)
3. Decreases excitability of latent pacemakers
12
Q
What are the effects of changing the funny current or max diastolic potential (MDP) on rate of action potential generation in SA nodal cells? In other words, what do these curves mean?
A
- A: “normal” action potential profile in cells that have pacemaker potential, e.g., SA nodal cells
- B: shows effect of decreased I(funny) current that can occur, for example, via increased PARA activity or decreased SYM activity
- C: show effect of more (-) max diastolic potential “MDP” (takes a longer time for funny channel to allow current to reach threshold) -> can also occur via increased PARA activity, mediated by increased K channel activity
- In both B and C, it takes a longer time to reach the threshold potential (TP) for activating Ca channels, providing lower heart rate; SYM activity does exact opposite of effects induced by PARA activity
- All of these things are REVERSIBLE
13
Q
What is the effect of changing TP on rate of action potential generation in SA node cells?
A
- A: “normal” profile in cell with spontaneous depolarization
- B: cell in which threshold potential is less (-), i.e. it takes more (+) potential to trigger activation of Ca channels that carry current for electrical depolarization
- Can occur under influence of increased PARA activity, via decreased cAMP levels -> end result is it takes longer to reach threshold and HR is reduced
- Exact opposite happens with activation of SYM activity, which increases cAMP, causing greater reactivity of Ca channels
14
Q
What does this graph tell you about the speed of conduction of electrical activity in the heart? What is dromotropy?
A
- Takes only a few milliseconds for depolarization wave to travel from SA node to AV node
- 40 milliseconds for depolarization wave to cross AV node (principal place to slow down rate of ventricular contraction)
- Bundle of His: speed of conduction picks up again
- SYM (NE, E) speeds up; PARA (Ach) slows down conduction speed
- Dromotropy: increased speed of conduction
15
Q
What does this graph tell you about the effect of autonomic tone on heart rate?
A
- Typical normal HR at rest 60 to 70 beats/min, but intrinsic rate of activation of SA node much higher, ~100 beats/min bc tonic SYM, PARA activity at rest
- Atropine (cholinergic M2 receptor antagonist) INC HR to 120 bpm at max dosage -> strong tonic PARA
- Propranolol (beta adrenergic antagonist) drops HR to about 50 bpm -> modest tonic adrenergic activity
- If all autonomic NS activity blocked by giving both atropine and propranolol, the intrinsic SA node rate is uncovered -> about 100 bpm in this case
16
Q
How is Ca involved in cardiac muscle contraction?
A
- IC Ca the critical activator of cardiac muscle contraction similar to that in all other muscle types
1. Ca channels activated in plateau phase (2)
2. Shortly after IC Ca reaches peak conc, contraction begins
3. Subsequently, IC Ca decreased, contraction returns to baseline - Ca enters cells + released from IC sarcoplasmic reticulum bc entry of Ca via channels insufficient to activate contractile machinery by itself
- Ca binds troponin C, myosin and actin interact, & there is a stroke/power event -> ventricular force
17
Q
What are the two factors regulating the strength of muscle contraction?
A
- Intracellular Ca levels during action potential
1. Contraction is graded based on IC Ca conc
2. Free Ca (binds troponin C) and total Ca in the cell -> higher the IC free Ca conc = greater ventricular force of contraction - Initial length of cardiac fibers, which determines sensitivity of myofilaments to Ca
18
Q
How is IC Ca regulated?
A
- Calcium influx into cells
- Calcium release from sarcoplasmic reticulum
- Calcium uptake by sarcoplasmic reticulum -> so the ventricle can relax
- Calcium efflux (that which came in)
19
Q
Describe Ca metabolism in myocardial cells.
A
- Voltage operated Ca channels open upon cell membrane depolarization
- Ca binding to RyR (ryanodine receptor) in SR releases sufficient Ca for myofilament activation
- Ca removed via cell mem exchangers and pumps, the SR and mito (mito least important in this regard, but may play role long-term, as Ca reservoirs)
- Ca actively pumped against conc gradient into SR, and out of cell (ATP-dependent)
- Efflux via Na-Ca exchanger -> indirect active transport (anti-port fashion); possible due to strong electrochemical gradient for Na to enter cell (generated by NA/K ATPase)
20
Q
How is cardiac cell activity controlled by catecholamines and Ach?
A
- Catecholamines accelerate rate of: 1) cardiac contraction (inotropy), 2) IC Ca decline, & 3) cardiac relaxation (lusitropy)
- Phosphorylation of troponin I decreases its affinity for Ca, which is picked up by SR at accelerated rate via phospholamban phosphorylation by PKA
- Increases SR Ca content -> inotropic effect of catecholamines mediated by increased SR content and I(Ca) channel phosphorylation by PKA; some evidence indicates that phosphorylation of RyR is associated with greater Ca release from SR
- When Ca & Ryanodine channels phosphorylated, they transport more Ca (becoming more active)
- Increased SYM activity = increased contraction rate and force, and ventricular relaxation rate
- Ach decreases cAMP (opposite of SYM) -> both work by manipulating same IC messenger (cAMP)
- As SYM goes up, in most cases, PARA goes down, and vice versa
21
Q
Why is muscle length important in the generation of active cardiac fiber tension?
A
- Frank-Starling mechanism -> INC sarcomere length = INC active tension, up to physiological limit (maximum of the active tension curve)
- Making sarcomere longer causes greater active tension and resting tension
- More the ventricles are stretched, the greater the ventricular contraction
22
Q
What is preload? How is it affected by end diastolic volume (EDV)?
A
- Preload: degree of filling of ventricles before they contract
- Up to a physiological limit, normal heart will pump out any end diastolic volume (EDV) and reach same systolic volume (ESV) -> INC stroke volume
1. SV = EDV - ESV - More volume = more stretch -> INC stroke volume
23
Q
Frank-Starling mechanism: end diastolic volume determines stroke volume -> KNOW THIS.
A
Good job!
24
Q
How does an increase in length translate to increased cardiac force generation?
A
- Fast response to stretch, involving increased Ca sensitivity of myofilaments by stretch -> as you stretch filaments, they become more sensitive to Ca (> force for similar level of Ca)
1. More Ca coming in + more sensitivity - Slow response to stretch, involving activation of Ca channels by stretch
25
Q
What does this graph tell you about fiber length and Ca sensitivity?
A
- Provides Ca-tension relationship for cardiac fibers at increasing or decreasing lengths
- INC fiber length makes them more sensitive to Ca, whereas the inverse is true for shortening
- Contributes to INCREASED VENTRICULAR FORCE generation
26
Q
What is Ohm’s Law? Explain.
A
- Q = DeltaP/R
- Flow between any two points is determined by the pressure difference between the two points, divided by resistance
-
NOTE: when flow is turbulent, Ohm’s law no longer applies
1. Streamline flow: velocity center > velocity edge
2. Turbulent flow = chaotic velocities
28
Q
Know this. Also, why do we control things by changing resistance and not DeltaP?
A
- Figure shows the approximate blood flow volumes at rest
1. Note that kidneys, GI, skeletal muscle get highest blood flow (at 25%) - Blood flow is the currency of the system; need it for function -> this is why we control things by changing resistance and not DeltaP; want to be able to make changes in terms of individual organs, and not the whole system
29
Q
What are the implications of this table?
A
- Table shows that changes of blood flow to different organs can vary dramatically
- Example: blood flow went up in organs that had INC function during physical activity -> ACTIVE hyperemia
- At same time, blood flow went down in other organs to DEC demands on heart via INC SYM activity
- Regulated via VASODILATION (delta P for all organs is the same -> ONLY THE RESISTANCE CHANGES)
- Brain has a very steady total blood flow throughout life (auto-regulation, so it opposes any changes in attempts to alter its blood flow)
- Blood flow diverted to skin to help keep body temp constant (you will be hot during physical activity, so increased blood flow here helps cool the body)
30
Q
What are the determinants of resistance in laminar flow?
A
- Higher resistance with INC viscosity, tube length
- Just a two-fold INC in radius will DEC resistance 16-fold
31
Q
What is the significance of Reynold’s #?
A
- Reynold’s = (diameter x velocity x density) / (viscosity)
1. >400 = local vortices at branches, arches
2. >2000 = turbulent flow (high resistance -> reduced flow) - Laminar flow at LOW Reynold’s #’s bc viscous forces dominant -> smooth, constant fluid motion
- Turbulent flow at HIGH Reynold’s numbers; inertial forces cause chaotic eddies, vortices, flow instability
1. Turbulent flow = noise (murmurs)
32
Q
How does the hematocrit affect viscosity, and the load on the heart?
A
- Greater the hematocrit, greater the viscosity
- So, in polycythemia, all other variables being equal, there will be greater resistance to flow than in the normal condition and the load on the heart will be greater
36
Q
How is blood flow linked to metabolic need?
A
- Greater rate of metabolism = greater blood flow
- NOT a linear relationship bc tissues have “blood flow reserve” and, at increased metabolism, can draw on reserve w/o increasing blood flow significantly
1. Most organs “over-perfused” at rest, so don’t need much added flow w/sm INC in metabolism - As rate of metabolism continues to increase, rate of blood flow increase matches demand for blood flow
37
Q
How is blood flow related to oxygen tension?
A
- Lower the arterial O2 conc, greater the blood flow
- Inverse relationship
- Shape of the curve (concave) similar to that relating blood flow to metabolism -> you need to have O2 to fuel metabolism
39
Q
What is the relationship b/t the time of interruption of blood flow, and the intensity/duration of reactive hyperemia?
A
- Graph shows the effects of increasing periods of decreased blood flow from constriction of arteries
- Increase in blood flow that occurs on release of the constriction is “reactive hyperemia”
- Magnitude and duration of hyperemia related to the length of reduction of blood flow, aka ischemia -> the longer the ischemic episode, greater the magnitude and duration of the blood flow during hyperemia
45
Q
What is blood flow autoregulation?
A
- Capacity of blood vessels to oppose changes in blood flow imposed by changed blood pressure
- W/o auto-regulation, greater delta P = more blood flow -> but, with auto-regulatory capacity (some tissues have more of this than others), resistance will increase to counteract increased perfusion
- Generally more effective when perfusion low than high
- BRAIN is really good at auto-regulation
49
Q
What is the relationship between SYM activity and vascular resistance?
A
- SYM activity at rest is greater than zero, i.e. there is TONIC ACTIVITY -> allows DEC and INC of SYM
- Convex curve, showing that, at low levels of SYM activity, relatively small increase of SYM activity induces large INC of vascular resistance
- SYM effects can be opposed by local effects -> one will win out (i.e., in the case discussed earlier where you want more perfusion to some, but not all, organs)
1. Two mechanisms that operate separately, allowing more fine-tuning
56
Q
Why is ventricular blood flow out of phase in comparison to that of other organs?
A
- GREATEST BLOOD FLOW IN DIASTOLE
- Ventricular contraction during systole mechanically compresses resistance arteries and increases vascular resistance, reducing or even momentarily reversing coronary blood flow on left side of heart
1. Resistance inversely related to fourth power of radius, so momentary ischemia during systole causes reactive hyperemia in diastole (even though DeltaP DEC bc R DEC) - Important for ventricular pressures to remain relatively low during diastole, so heart can be adequately perfused during this period
- Similar effect on right side of the heart, but it is of much lower magnitude
57
Q
What is significant here?
A
- Resistance of coronary vessels greater than that in resistance vessels of other organs in systole
- This is because of mechanical compression of coronary arterioles during systole
60
Q
Describe this graph, and what it says about blood flow to skeletal muscle during rhythmic exercise.
A
- Rhythmic exercise induces mechanical compression of arteries in skeletal muscle: during e/compression, blood flow DEC bc of INC resistance, due to reduced radius of blood vessels, induced by compression
-
Reactive hyperemia after each ischemia episode + overall active hyperemia bc INC muscle function -> mean blood flow INC as intensity of exercise INC
1. Active is red line, and reactive the rhythmic spikes (constricting blood vessels when skeletal muscles are clenched)
62
Q
What is the splanchnic circulation? How is it controlled?
A
-
Splanchnic: hepatic, pancreatic, splenic, intestinal
1. Liver: portal system provides 1,100 mL/min of BF, & arterial provides 350 mL/min (30% of CO)
2. Spleen: reservoir of RBC’s and plasma volume; can be released w/exercise or low BP - Active hyperemia: local metabolites + hormones released in digestion play major roles in controlling intestinal flow
- Extrinsic control: SNS, which can help attenuate hypotension (also a__uto-regulation)
- Graph: initial INC of vascular resistance w/feeding due to INC SYM activation that occurs when we start eating; large DEC of splanchnic resistance later an active hyperemic event bc INC splanchnic function
63
Q
How is blood flow regulated in the skin? Why?
A
- Almost entirely controlled by CNS -> blood flow to skin increases when ambient temp rises
- Heating the trunk via heating pad on abdomen INC cutaneous blood flow by DEC SYM activity to arterio-venous anastomoses and DEC resistance to BF
- Brings warm blood to surface of body, allowing the dissipation of heat into envo
- Eventually the core temp, i.e. brain temp begins to rise, causing an even greater INC of cutaneous BF
- Cooling the trunk, however, by placing ice on the abdomen is immediately sensed by hypothalamus, causing constriction of arteriovenous anastomoses, and decreasing skin blood flow
64
Q
Why is the anatomy of cutaneous blood vessels important?
A
- Arteriovenous anastomoses are under the control of SYM activity, which is controlled by hypothalamus
- In subcutaneous tissue, there is withdrawal of tonic SYM activity when there is an INC in temperature, bringing blood to the skin, and causing FLUSHING
1. This allows for heat release and moderation
