Heart 6: Myocardial Excitation-Contraction Coupling Flashcards Preview

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Flashcards in Heart 6: Myocardial Excitation-Contraction Coupling Deck (65):

Where are t-tubules and what do they do?

few t-tubules in atrial but prominent t-tubules in ventricular muscle. brings the AP down to deeper parts of the cell.
ventricular cells large -100 microns in diameter. 50 microns long.


How is Ca release activated from SR? Is this an electrical event?

NOT electrical activity that opens SR Ca release channels - its the L type Ca current that's activated during plateau.
L-type current allows Ca to come in and that in turn activates the release of Ca from ryanodine receptors on SR and that Ca goes to actin and myosin filaments to activate contraction


Describe the Ca induced Ca release. What is the trigger? How can that be modulated?

Ca induced Ca release - considered amplification mechanism. means chemically you can augment or interfere with mechanism at many steps. if you increase size of Ca current you can increase the amount of Ca released and increase contraction strength. If you decrease Ca current, decrease Ca being released. L-type Ca current is trigger for SR calcium release … can modulate that with autonomic nerves or with drugs clinically


What are some bad side effects of slow Ca channel blockers someone might be taking for vascular system to reduce hypertension (high bp)?

they can affect the heart and cause negative ionotropic effects and reduce cardiac output of the heart.
(SR Ca release depends on amount of Ca in the SR)


What are the two main points of regulation that determine contraction strength of the heart?

1) Ca influx (can be regulated)
2) amount of Ca in SR (can be regulated)

-can modulate with sympathetics and parasympathetics. NS can modulate indirectly and alter contraction.


Where are Ca channels located?

not on surface membrane. most are located along t-tubules. sarcolemma doesn't contain many Ca channels. mostly they are located right across from SR ryanodine receptors- short distance to t-tubules.


Where does Ca influx occur? What happens after influx?

occurs in these t-tubules across from SR. Ca influx releases Ca from terminal cisternae of the SR and that goes to troponin and activates actin and myosin


What happens at the end of contraction? How does the Ca induced Ca release turn off?

Ca being removed from troponin has to be taken back into SR - that is SERCA or Ca-ATPase (SR Ca ATP pump which brings Ca back into SR at end of contraction and refills SR)


What mechanism may contribute to heart failure involving SERCA?

SERCA/ Ca-ATPase activity is depressed. may contribute to congestive heart failure- SR not taking Ca back in normally so SR not loaded and less Ca available for contraction strength

heart failure- in ability of heart to generate normal cardiac output due to abnormal Ca handling

congestive heart failure has to do with Ca handling (hypertension will lead to congestive heart failure but mechanism is complex and not well known)


What is Ca handling?

Ca influx, Ca release, Ca uptake back to SR, Ca binding to troponin ... anything to do with Ca.


Describe a summary of the normal EC coupling mechanism.

Ca influx through L type Ca current, Ca induced Ca release from SR, binding of Ca to troponin, interaction with actin/myosin, at end of contraction re-uptake of Ca by SERCA back into SR.


How do we modulate SR Ca release? / contraction of the heart?

beta stimulation (NE from sympathetic nerves which is catecholamine) ...could be epi. circulating in blood (comes from adrenals. and is a hormone) NE is neurotransmitter.
beta receptors are Beta 1 on the heart

convert ATP to cAMP through adenyl cyclase which is enzyme connected to g-proteins. cAMP is 2nd messenger that activates lots of phosphokinases -in heart its pKa. body activates signaling mechanisms by phosphorylation- which changes function of structures. phosphorylation of Ca channel will increase the number of Ca channels that will open … also phosphorylate protein called phospho-lam-ban (PLB)- functions to inhibit ATPase, the SERCA. puts a break on SERCA normally. when its phosphorylated it removes the inhibition and it speeds up the activity of the ATPase activity (SERCA) speeds uptake of Ca back into SR


Describe the function of Phospholamban.

PLB normally present in cell and puts break on SERCA and puts break on uptake of Ca. when beta stimulation comes along and phosphorylate PLB then it accelerates the uptake of Ca, removes inhibition.


What happens if you phosphorylate Ca channels?

open up more Ca channels if you phosphorylate them so more Ca comes in and you have a greater trigger for Ca release and if you remove the break on ATPase and allow more Ca to be taken back into SR, then you've enhanced the amount of Ca available for contraction.


What other effect does beta stimulation have on troponin-I?

phosphorylates troponin I which reduces the binding or affinity of Ca for troponin-C
why would it reduce the affinity of Ca for its troponin binding site? -turns out that catecholamines enhance rate of relaxation of heart. heart relaxes more rapidly in presence of beta stimulation… if you increase HR then the entire cycle has to contract in time, happens more quickly, relaxation into diastole more rapid to allow more time for filling. relaxation of heart is just as important as contraction. relaxation of heart is critical for filling.


What is diastolic/systolic heart failure?

diastolic heart failure- can't fill heart normally (heart can't relax enough to allow filling)
systolic heart failure- heart can't generate enough force to pump blood during systole.


What 2 mechanisms promote relaxation during beta stimulation?

Phosphorylates troponin-I and reduces affinity of Ca for troponin C. v imp. mechanism that helps heart to relax quickly - allows Ca to come off troponin-C during relaxation in presence of beta stimulation.

other mechanism that also promotes relaxation during beta stimulation is same mechanism that fills Ca in SR and thats SERCA…by enhancing SERCA its pulling Ca out of cytosol off actin filaments and pulling back in SR allowing heart to relax. so SERCA is also critical for relaxation and is accelerated during sympathetic nerve stimulation


What are the two mechanisms for relaxation?

2 mechanisms for relaxation: reduction of Ca affinity for troponin C and enhanced uptake of Ca into SR.

phosphorylation of PLB… loads more Ca into SR but also enhances rate of taking Ca off actin filaments and puts it back in SR


What Ca goes back into the SR? What happens to the rest of the Ca?

only the Ca released from SR gets taken back up... the Ca that came in during AP (L-type Ca) doesn't contribute to contraction significantly

Ca that came in during Ca current has to be taken back out … Na/Ca exchange critical. exchanger brings out Ca in exchange for Na.


How did they discover what Ca contributed to contraction?

can give cell ryanodine… (comes from a root from plant from trinidad) … v specific for blocking SR Ca. poison… SR Ca release releases all the Ca necessary for contraction… inhibit ryanodine receptor and you stimulate AP and get Ca influx it doesn't do anything. doesn't cause contraction.


If Ca release is inappropriate and releases Ca in after the AP what will happen?

it will stimulate Ca efflux and Na influx and thats a DAD. under normal conditions its a normal mechanism to bring Ca out of cell (Na/Ca exchanger)


Which mechanism in the heart is primarily responsible for reducing cytosolic Ca?
Na/Ca exchanger or SERCA?

SERCA. taking Ca out of cytosol and putting it back in SR. (SR Ca is not cytosolic Ca)


Which mechanism in heart is responsible for removing Ca from the cell?

Na/Ca exchanger


What effect do digitalis/glycosides have on contraction of the heart? What is the mechanism?

-increase contraction strength

-it causes a few ATP molecules to be inhibited. reduces ATP a little bit. function of ATPase is to pump Na out. so if you inhibit it a bit you will have more Na inside the cell. what does that do to the exchanger? exchanger runs off gradient of Na flowing into cell passively so if you reduce the gradient of Na its more difficult for Na to flow into cell and more difficult for Ca to come out of cell. so Ca accumulates inside cell and gets sucked up into SR and SR gets overloaded w Ca and then you run into these DADs. SR gets overloaded w Ca, then inappropriately releases that Ca after AP, re-stimulating the Na/Ca exchange causing DADs.


Which cell would contain more mitochondria; skeletal or cardiac? Why?

40 percent of volume of cardiac muscle is mitochondria. so much mitochondria in cardiac muscle- not in skeletal.

heart req enormous amount of ATP which comes from mitochondria. marbled throughout structure of myocyte which takes away from myocytes’ ability to contract really hard bc these things don't contract. so have to give up some of your contraction in order to make room for mitochondria- but does give you ready supply of ATP everywhere you use ATP ..like myosin for cross bridge cycle.


Where can you find SERCA in a cardiac cell?

lots of it around nucleus and striated patterns, so a lot around Z line and in longitudinal streaks. SERCA located through the cell. so anywhere theres a Ca theres a SERCA that can pick it up and grab it and pump away to Ca stores.


Where does most Ca handling take place?

all Ca handling happens in strings of SR. Z line of sarcomere. near Z line is where t-tubules come down into cell. closeup slide8


Where is SR in relation to t-tubule?

SR wraps around t-tubule. Ca channels in t tubule dumping Ca and right next to is SR where ryanodine receptors are. they sense Ca and get Ca induced Ca release. Ca hits SR and that releases whole bunch of Ca.


How much Ca comes out of t-tubule? SR?

20 percent hitting adjacent myofilaments comes out of t-tubule. 80 percent released by Ca induced Ca release


How do you stop Ca induced Ca release?

get wave of positive reinforcement where Ca comes out and activates other Ca channels. but empty out SR of Ca and built in inactivation mechanisms that turn off ryanodine receptors after time.


What are dihydropuradine receptors (DHPRs)? What do they do? How is the mechanism different in skeletal vs cardiac cells?

these are same as L type channels
-lets Ca out of t tubule and come over to cleft where hits ryanodine receptor to let Ca out of SR. skeletal muscle referred to more as DHPR but same channel. in skeletal muscle there is mechanical coupling. so in skeletal muscle voltage change itself transmitted from DHPR to ryanodine receptor. here you need Ca outside the cell that comes in and gives Ca induced Ca release. not voltage dep. at all. entirely Ca dependent. if you have 0 Ca outside the muscle will not contract, but skeletal will.


What is the function of the sarcolemma?

propagation of AP
control Ca influx into the cell via activation of slow inward Ca current.


What is the function of transverse/t-tubules? Where is it located?

transmit electrical activity to cell interior. Located at Z lines.


What is the function of the SR? What are the two components and their functions?

intracellular Ca storage site, Ca stored in between beats, released from compartment quickly

terminal cisternae- Ca influx triggers opening of Ca release channels to initiate contraction

longitudinal cisternae- site of Ca re-uptake to initiate relaxation


What is the function of troponin C?

Ca receptor on contractile actin protein

sensor for Ca in thin filaments. when Ca is high it senses it and binds to Ca and activates thin filaments so myosin heads can cycle and give contraction and give shortening of sarcomeres.


Describe the mechanism for EC coupling in cardiac muscle.

1. Action potential conducts along surface membrane and down into T-tubules.
2. Depolarization of T-tubules activates Ca2+ influx via slow inward Ca2+ current.
3. Influx of Ca2+ binds to and opens SR Ca2+ release channels (ryanodine receptors).
4. Ca2+ release from SR binds to troponin C to initiate cell contraction.
5. Process known as Ca2+-induced Ca2+ release (CICR).
6. Contraction is maintained as long as cytosolic Ca2+ remains elevated.
7. Relaxation is initiated when cytosolic Ca2+ is removed by:
a) SR Ca2+ uptake ( 80%)
b) Ca2+ efflux via Na/Ca exchange ( 18%)
c) Ca2+ efflux via sarcolemmal Ca2+ pump ( 2%).


How is cytosolic Ca removed?

a) SR Ca2+ uptake ( 80%)
b) Ca2+ efflux via Na/Ca exchange ( 18%)
c) Ca2+ efflux via sarcolemmal Ca2+ pump ( 2%).

will initiate relaxation


If you give verapamil for the heart, why won't it affect skeletal muscle?

bc the L type Ca current in skeletal muscle doesn't bring in Ca. not a part of EC coupling mechanism.


Compare the size of cells in cardiac vs skeletal muscle.

cardiac- small cells (50-100 micrometers?)

skeletal- fibers can run full length of muscle


Describe how cells are connected in skeletal vs cardiac muscle.

cardiac- syncytium -electrically coupled via gap junction connections

skeletal-individual muscle cells

so if you stimulate heart at one point-stimulate whole heart bc gap junctions thats why aberrant pacemakers stimulate whole heart. not just one cell. aberrant pacemaker …group of cells firing together spreads AP all over heart. whole basis of artificial pacemaker- produced by screwing electrode right into myocardium of right ventricle. one point stimulated and stimulates whole heart. bc all cells electrically connected… could never do that in skeletal bc each is individual. each fiber has a nerve going to it.


How are cardiac/skeletal muscle cells activated?

cardiac- activated by cell to cell conduction (NO neuromuscular junctions)

skeletal- activated by neurochemical transmission (Ach) at neuromuscular junctions
-Ach released from individual nerve and that nerve stimulates that one fiber.


Describe what contraction depends on in cardiac vs skeletal muscle.

cardiac- contraction dependent on Ca influx (Ca induced Ca release)

skeletal- contraction NOT dependent on Ca influx (voltage-sensor of Ca channel)

contraction dep. on Ca induced
Ca release in cardiac but in skeletal Ca channels acts as voltage center. contraction not dep. on Ca. will contact without Ca in skeletal.


How is contraction amplitude regulated in skeletal vs cardiac muscle cells?

cardiac- contraction amplitude regulated by Ca influx via slow Ca current and SR Ca content

skeletal- contraction amplitude regulated by frequency of AP and central recruitment of muscle fibers

When you activate skeletal muscle to pick something up- have thousands of AP streaming down nerve to skeletal muscle down axon and number of Ap determining amount of Ach. released and that det. if muscle will summate or not. contraction strength - can only happen with short AP. coded by frequency or det. by central recruitment of muscle fibers in brainstem… use appropriate amount of muscle to lift heavy weight


Describe summation and tetanus in skeletal vs cardiac muscle.

cardiac- no summation or tetanus

skeletal- summation and tetanus generates maximal tension


Describe the density of mitochondria in cardiac vs skeletal muscle?

cardiac- primarily aerobic metabolism (density of mitochondria approx 35 percent)

skeletal- significant anaerobic metabolism (density of mitochondria- approx 2 percent)


Why does the heart need so much more O than skeletal muscle? What happens if you sleep on arm at night and cut off blood flow?

needs Oxygen to generate ATP. main job of cardiologist is to manage O consumption in patients with coronary disease or heart failure. without O you wont generate ATP and muscle strength. if cut off O supply to heart for short time it becomes ischemic and infarcts.

skeletal muscle- only 2 percent mitochondria, run off glycolysis and don't infarct skeletal muscles… sleep on arm at night and cut off blood flow and tingly bc pH changing and nerves changing to anaerobic glycolysis and prod. ATP anyway.


What are catecholamines?

Describe the mechanism.

norepi. and epi.
positive ionotropic agents

1) binds to β-adrenergic receptors (primarily β1) on surface membrane
2) acts via Gs to activate adenylate cyclase to increase cAMP
3) cAMP activates cAMP-dependent protein kinase A (PKA)
4) PKA phosphorylates:
a) Ca2+ channels to increase Ca2+ influx.
b) phospholamban to increase SR Ca2+ uptake (enhances relaxation).
c) both mechanisms increase Ca2+-induced Ca2+ release (increase strength of contraction).
d) enhances time course of relaxation (see b)


What does contractility specifically refer to?

What kind of ionotropic effects does sympathetic autonomic stimulation result in?

intracellular Ca. lots of things that can change contraction strength of heart but Ca is just one of them. can change strength of contraction of heart w/o changing Ca. but change in Ca is always change in contractility.

autonomic stimulation through symp. NE (neurotransmitter) epi- hormone. cause positive ionotropic effects (ionotropic=contractility!!! change in contraction strength based on Ca) speeds up relaxation. symp. nerve stimulation increases strength of contraction (stroke volume) and enhances relaxation to allow next cycle to occur bc also increasing HR.


Describe the reason cardiac glycosides (ex: digitalis) are prescribed.

What is the mechanism?
What is the effect on contraction and relaxation?

positive inotropic agent used in congestive heart failure.

1) inhibits Na-K pump.
2) increases intracellular [Na] and thereby decreases [Na] gradient.
3) slows Ca2+ extrusion via Na-Ca exchanger and increases intracellular [Ca].
4) increase in SR Ca2+ content leads to greater SR Ca2+ release and contraction.

doesn't enhance relaxation! not Phosphorylating anything…just increasing intracellular Ca.
(increase in contractility not always associated with increase in relaxation )


What does digitalis do to the HR?

What does digitalis do to HR? turns out that digitalis actually slows HR down through increased vagal nerve stimulation. increase contraction of strength and also reduces HR (so no need for digitalis to increase relaxation bc its not increasing HR)


Why is digitalis good for congestive heart failure?

bc one problem w congestive heart failure is heart is not efficient… not handling Ca normally or using O efficiently. can’t give NE to increase cardiac output bc its going to increase O consumption and problem with someone with heart failure is not handling O well and last thing you want to do is put stress on heart to increase O consumption even more.

digitalis- inhibits passive ion changes. inhibiting ATP which uses O and changing ionic balance and enhancing intracellular Ca almost for nothing. when increase contraction strength with digitalis you use O but not as much as you would use with NE

glycosides increase O consumption bc increase strength of contraction but they increase it far less than something like NE. also decreases HR- HR directly correlated with O consumption. problem is DADs though…


Why do you use so much oxygen when exercising?

exercise use a TON of O bc you’re phosphorylating the Ca channel, you’re phosphorylating which takes ATP… cAMP due to conversion of ATP to cAMP) so has to do with management of O consumption.


Describe the 3 main Ca channel blockers and what they are used for.

verapamil, diltiazem, nifedipine

Clinically used as vasodilators (smooth muscle) and anti-arrhythmic agents (cardiac).

verapamil- supraventricular tachycardia
diltiazem- vascular smooth muscle to reduce bp
nifedipine- arrhythmias

they are Ca channel blockers and are vasodilators to reduce or relax vascular smooth muscle and are anti-a bc they will slow conduction though AV node and they block supra ventricular tachy- WPW- when re-entry set up going antegrade through AV node and retrograde though accessory pathway. going around and around. tachycardia that involves atria and ventricle. prevent it by increasing refractory period of AV node. thats what Ca channel blocker does. give verapamil and prevent rapid activation of AV node- filter impulses more by increasing refractory period. that supra-ventricular Tachy. dep. on slow pathway and if you can slow conduction though that pathway you can block re-entry


How can you block supraventricular tachycardia? Describe 2 ways.

Ca channel blockers- anti a bc they slow conduction through AV node. block re-entry by increasing refractory period of AV node. prevent rapid activation of AV node and so filter impulses more. (SVT dep. on slow pathway and if you can slow conduction through that pathway you can block re-entry)

slow conduction through AV node by stimulating vagus


How can you stimulate the vagus?

how to stimulate vagus? maneuvers at home to increase vagal stimulation. cold compress and put it on face.. diving receptors on face. and seals have v strong diving reflex when dive heart rates goes down by 6 beats per minute to conserve O. cold compress on face will slow HR and can break supra-ventricular tachycardia. thats the most benign way of doing it.

also clinically - stick finger under mandible and press on carotid - (could break off plaque and get a stroke) but carotid sinus senses bp. stimulating increase in bp on baroreceptors. stretch receptors. press on it and sends impulse to stimulate vagus. can also break supra-ventricular tachy.

valsalva…”bear down” straining… increase in pressure in thorax against closed glottis. increases vagal nerve activity. that’s why shouldn't do what lifting weights - increases vagal nerve activity and reduces cardiac function -not what you want. so breathe out when lift heavy weight.


What is the mechanism of Ca channel blockers?

-mechanism of slow channel blocking agent- don't use to block contraction in heart use them to dilate vascular smooth muscle or block arrhythmias.

1) blocks Ca2+ influx via Ca2+ channels.
2) decreases in SR Ca2+ release and SR Ca2+ content which leads to less contraction in vascular smooth muscle (vasodilator).
3) cardiac anti-arrhythmic effects due to inhibition of slow inward Ca2+ current which inhibits conduction of AV node action potential (blocks SVT).
4) unwanted side effect: negative inotropic effects on heart.


What is the force-frequency relationship?

Give a clinical example.

The beating rate and rhythm of the heart (cycle length) influences cardiac contraction amplitude by altering contractility. Changes in cycle length alter the TIME available for intracellular Ca2+ handling, which alters contractility.

Clinical Example: variability of radial pulse amplitude during atrial fibrillation.
Slide 19

(force of heart contractility of heart is related to interval between beats. becomes imp. clinically with diagnosing a-fib)


Why would the amplitude for PVC contraction be smaller than normal?

premature beat, contraction strength (amplitude) for PVC contraction smaller than normal bc interval between beats shorter than normal and Ca handling of cells cut short. heart beating at certain rate.. all certain rates contingent on freq. of heart. premature beat and everything cut short- less timing for recovery of channels less time for filling of SR and contractility of heart is reduced bc Ca is reduced. so premature beat always has smaller than normal contraction. usually so small that it does not generate enough force to open the aortic valve and pt taking pulse feel like they skipped a radial pulse. earlier premature beat comes less likely the aortic valve will open.


What is the compensatory pause with a PVC?

compensatory pause (extra beat actually) time factor…all mechanisms have more time to recover so higher amount of Ca in SR…. get much stronger contraction (called post extra systolic potentiated beat). thats the “thumping” pt feels in chest. thats a palpitation. w next beat back to normal cycle next beat comes down and strengths out again bc Ca restored.


Describe a simulation of force-frequency relationship from 60/min to 120/min back to 60/min.

120 beats per min- interval should be half of what it was. like premature beat. if keep at short cycle length, increases and now positive staircase in contraction strength and reaches new steady state A bc of greater amount of Ca coming in into cell. at higher HR more Ca comes in per minute. readjusts to new cycle length and has stronger than normal contraction based on cycle length. stop stimulator and now pause and thinks cycle length is still high but its not so get much stronger contraction bc have more Ca inside cell. over time comes down back to rest. negative staircase. readjusted to longer interval. force of heart (contractility of heart) is somewhat dep. on interval between beats. becomes important in a-fib.
Slide 19.


Why is the force-frequency relationship important in a-fib?

interval between ventricular beats is variable. irregularly irregular. means force of contraction of each beat is diff bc interval is diff. shorter interval get smaller contraction. longer intervals get stronger contraction. use clinically.
Slide 19.


In the force-frequency relationship describe the positive stair-case (treppe) and mechanism.

as heart rate increases the strength of contraction increases

1) greater Ca influx per unit time and less time for Ca efflux via Na/Ca exchange

2) increased SR Ca content and SR Ca release; larger contraction strength


Describe the negative staircase and mechanism.

decrease in HR results in decrease in contraction strength.

1) less Ca influx per unit time and more time for Ca efflux
2) less SR Ca content

therefore smaller Ca-induced Ca release; smaller contraction


Describe the force-frequency relationship in regards to premature beat. (Mechanism)

smaller than normal contraction

1) less time for recovery of slow inward Ca current
2) less time for recovery of SR Ca release channels
3) less time for re-distribution of Ca stores in terminal cisternae of SR

therefore smaller Ca induced Ca release; smaller contraction strength


Describe post-extrasystolic potentiation (PESP).

=stronger than normal contraction of the beat following a premature beat

1) more time for recovery of Ca current
2) more time for recovery of SR Ca release channels
3) more time for re-distribution of Ca stores into terminal cisternae of SR

therefore larger Ca induced Ca release; larger contraction strength