Lecture 7: Cardiac Muscle, Cellular Control of Myocardial Contraction

Question 1

What is Ca-induced Ca release?

Answer 1

When ECM Ca opens the RyR

Question 2

What is E-C coupling?

Answer 2

Excitation-contraction coupling

Question 3

What is a triad?

Answer 3

One t-tubule sandwiched between two SRs

Question 4

What are the foot proteins?

Answer 4

The ryanodine receptors

Question 5

What serves as the source for intracellular calcium?

Answer 5

1. extracellular Ca

2. Ca from the SR (calcium binding to ryanodine receptor releases this shit)

Question 6

What is the relationship between T-tubles and SR membrane?

Answer 6

T-tubules (green) and SR membrane (red) are always close together

Question 7

In cardiac and skeletal muscle, what initiates contraction?

Answer 7

Ca binding to troponin, causing it to expose tropomyosin
Troponin has three parts
i. troponin T
ii. Troponin I (inhibits myosin binding)
iii. Troponin C (Ca binding sites

Question 8

Why is the heart muscle stiff during ischemia?

Answer 8

Because you need ATP to relax muscle (or to detach

The myosin)

Question 9

What is the dihydropyridine receptor?

Answer 9

The L-type calcium channel

DHPR because it is antagonized by DHP

Question 10

What are the key characteristics of the Na-Ca exchanger?

Answer 10

3 sodiums that go from outside-in
1 calcium ion that gets pumped to the outside
So it is electrogenic (can contribute to depolarization)
Removes calcium from myoplasm

Question 11

What is the function of creatine phosphokinase (CPK)?

Answer 11

Phosphorylates ADP so that Na/K pump has enough ATP

Question 12

What are the differences of calcium release between cardiac and skeletal muscle?

Answer 12

1. The cardiac AP and twitch are long vs. skeletal AP
2. cardiac muscle contraction decays within a few beats when Ca2+ is removed from bathing medium
   
   • skeletal muscle can contract hundreds of times in Ca free medium because all activator Ca is derived from SR
3. Although the cardiac twitch is not affected by stimulus size, autonomic input, heart rate and hormones affect contraction strength
   
   • Skeletal muscle twitch is NOT UNDER EXTRINSIC CONTROL
4. AP duration controls twitch duration in cardiac muscle ONLY
5. In skeletal muscle, activator Ca is released from SR by direct voltage dependent communication between T and SR membranes
   
   • In heart, activator Ca is released by Ca-induced Ca release
6. Active Ca ATPase pumps return Ca to the SR in both tissues
7. Cardiac muscle also has significant Na/Ca exchanger activity in surface of the membrane

Question 13

How does propranolol mediate the effect of catecholamines?

Answer 13

Propanolol is a beta blocker and prevents the positive chronotropic effect of epinephrine and norepinephrine

Question 14

What does chronotropic mean?

Answer 14

Affects that change the heart rate

Question 15

What does inotropic mean?

Answer 15

Affects the strength of contraction of the heart

Question 16

What happens when we take extracellular calcium away from the cardiac muscle vs. skeletal muscle?

Answer 16

No extracellular calcium = no contraction for cardiac muscle

No extracellular calcium = 100s of contractions for skeletal muscle

Question 17

Where does the calcium come from in cardiac vs skeletal muscles?

Answer 17

For cardiac, Ca comes through L-type calcium channels (aka DHPR) and it both contributes to intracellular Ca concentration as well as freeing the Ca from the SR
For skeletal muscles, there is a channel protein to ryanodine receptor interaction, so you don’t need calcium to bind in order for Ca to be released from the SR

Question 18

What are three possible alterations to pacemaking rate?

Answer 18

By changing the diastolic interval of the SA node (because this is most sensitive
1. Reduced rate of phase 4 depolarization
2. Less negative threshold
3. More negative maximum diastolic potential
All of which decreases heart rate

Question 19

What is the significance of being able to alter pacemaking rate?

Answer 19

Allows body to adjust to environmental factors

Altered in the diastolic interval

Question 20

How is heart rate modified by hormones and neurotransmitters?

Answer 20

1. epi and norepi (faster)

2. ACh (slower)

Question 21

What is the MoA of catecholamines?

Answer 21

Epi/norepi + GCPR
Adenylyl cyclase activation
Increased cAMP
Increased PKA
Opening of the Ca channel

Question 22

How is catehcholamine effect mediated?

Answer 22

Phosphodiesterase DEGRADES cAMP to AMP in order to stop the signal and slow down heart rate
Can also be inhibited by ACh at the pre-synaptic terminal (figure below)

Question 23

What is the MoA of ACh on cardiac muscle?

Answer 23

Binds to muscarinic GCPR which is a Gi
Gprotein then OPENS a potassium channel so that it is harder to depolarize (takes longer so SLOWS down heart rate)
Gi also inhibits adenyl cyclase and
Therefore inhibits cAMP
ACh can also be inhibited by NE
At the presynaptic terminal (figure to right)

Question 24

What are the three possible alterations in strength of contraction?

Answer 24

1. increased [Ca]
2. More sensitive to Ca
3. More force at each [Ca]

Question 25

What is the relationship between length of beat and strength of contraction? Why?

Answer 25

Inversely proportional The SHORTER the beat duration, the STRONGER the contraction Because shorter beat means less time to get Ca out of cytoplasm, which means more Ca ultimately stays in cytoplasm. This leads to stronger contraction.

Question 26

What is an intrinsic control mechanism?

Answer 26

If heart beats faster, it will beat more strongly ratio between influx:efflux is increased at faster rates Less time to get Ca out of cell more Ca total in the heart total as a result Therefore stronger contraction

Question 27

How does sarcomere lengths affect the strength of contraction?

Answer 27

Myofibril for cardiac muscle maintains a CONSTANT volume So when muscle is stretched, the thin and thick filaments get CLOSER because length and distance of filaments are INVERSELY RELATED This makes muscle more sensitive to Ca2+

Question 28

What is the rate staircase?

Answer 28

The inverse relationship between twitch duration and twitch strength NOT the same as the effect of catecholamines although the result is the same! Intrinsic vs extrinsic

Question 29

What are the intrinsic control mechanisms of the heart rate and contraction?

Answer 29

1. rate staircase (inverse relationship between twitch duration and strength 2. at higher beating rates, duration of contraction is shorter so that diastole has enough time to fill 3. post extra-systolic potentiation (when there is a premature beat called a extra-systole that is smaller in force that is THEN followed by enhanced contractions) 4. Frank-Starling Law Diastolic filling changes the starting length of myocytes, thereby eliciting an increased contractile response -more stretch = higher contractile strength

Question 30

What is the mechanism of the frank-starling law?

Answer 30

Due to the shorter titin in myofibrils

Question 31

What are the types of extrinsic control mechanisms?

Answer 31

1. Ca concentration 2. Na concentration (less Na outside means stronger contraction due to Na-Ca exchanger…less extracellular Na means less Na-Ca activity and more Ca that gets to stay in cell) 3. K concentration (elevated K = reduces AP duration and DECREASES strength of contraction 4. Catecholamines (can inhibit ACh) 5. Acetylcholine (shortens cadiac AP by increasing K permeability) and inhibiting NE 6. paracrine influences from endothelial cells like NO and endothelin-1

Question 32

What is the effect of potassium on the Action potential?

Answer 32

It makes the action potential shorter | Decreases strength of contraction

Question 33

What are the effects of catecholamine?

Answer 33

Binds to beta receptor Incease cAMP Increase strength of twitch and decrease duration of twitch Shifts concentration calcium-Tension curve to the right (so that means you get less force for a given amount of calcium…less sensitivity to calcium) HOWEVER, the amount of calcium released into the cell is by so much more that is overcompensates and therefore makes the contraction stronger

Question 34

What are the effects of Cyclic AMP?

Answer 34

Increases Ca entry from ECM to increase strength of contraction However ALSO increases pumping by SR (reuptake of Ca), which seems paradoxical…until you consider that if you have more Ca in SR from reuptake, that means more Ca gets released everytime the ryanodine receptor is opened Increased reuptake shortens the length of the twitch but also gives muscle more Ca reserve to increase its strength

Question 35

What is phospholamban?

Answer 35

It is a SR Ca pump that takes up Ca from the cytoplasm Phosphorylation of phospholamban will increase Ca reuptake in SR Phosphorylated by cAMP

Question 36

How do catecholamines decrease twitch duration?

Answer 36

1. increased SR reuptake of Ca | 2. Changes in affinity of troponin for Ca (phosphorylation of troponin I) allow Ca to dissociate faster

Question 37

What is heart failure?

Answer 37

``` The inability of the heart to supply sufficient blood flow to meet the body’s needs Common causes include: i. MI ii. HTN iii. valvular heart disease iv. cardiomyopathy ```

Question 38

What are potential mechanisms for heart failure?

Answer 38

Abnormal Ca release from RyR/intracellular Ca release channels caused by i. overactive sympathetic nervous system to compensate for failing heart ii. hyperphosphorylation of the cardiac RyR iii. hyperphosphorylated cardiac RyR leads to dissociation of CALSTABIN2 iv. loss of calstabin2 = leakage of Ca from SR during diastole v. thus leads to fatal arrhythmias

Question 39

What is calstabin2?

Answer 39

A protein that dissociates off the RyR when hyperphosphorylated and contributes to heart failure mechanisms