Flashcards in Lecture 7: Cardiac Muscle, Cellular Control of Myocardial Contraction Deck (39):
What is Ca-induced Ca release?
When ECM Ca opens the RyR
What is E-C coupling?
What is a triad?
One t-tubule sandwiched between two SRs
What are the foot proteins?
The ryanodine receptors
What serves as the source for intracellular calcium?
1. extracellular Ca
2. Ca from the SR (calcium binding to ryanodine receptor releases this shit)
What is the relationship between T-tubles and SR membrane?
T-tubules (green) and SR membrane (red) are always close together
In cardiac and skeletal muscle, what initiates contraction?
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
Why is the heart muscle stiff during ischemia?
Because you need ATP to relax muscle (or to detach
What is the dihydropyridine receptor?
The L-type calcium channel
DHPR because it is antagonized by DHP
What are the key characteristics of the Na-Ca exchanger?
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
What is the function of creatine phosphokinase (CPK)?
Phosphorylates ADP so that Na/K pump has enough ATP
What are the differences of calcium release between cardiac and skeletal muscle?
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
How does propranolol mediate the effect of catecholamines?
Propanolol is a beta blocker and prevents the positive chronotropic effect of epinephrine and norepinephrine
What does chronotropic mean?
Affects that change the heart rate
What does inotropic mean?
Affects the strength of contraction of the heart
What happens when we take extracellular calcium away from the cardiac muscle vs. skeletal muscle?
No extracellular calcium = no contraction for cardiac muscle
No extracellular calcium = 100s of contractions for skeletal muscle
Where does the calcium come from in cardiac vs skeletal muscles?
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
What are three possible alterations to pacemaking rate?
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
What is the significance of being able to alter pacemaking rate?
Allows body to adjust to environmental factors
Altered in the diastolic interval
How is heart rate modified by hormones and neurotransmitters?
1. epi and norepi (faster)
2. ACh (slower)
What is the MoA of catecholamines?
Epi/norepi + GCPR
Adenylyl cyclase activation
Opening of the Ca channel
How is catehcholamine effect mediated?
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)
What is the MoA of ACh on cardiac muscle?
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)
What are the three possible alterations in strength of contraction?
1. increased [Ca]
2. More sensitive to Ca
3. More force at each [Ca]
What is the relationship between length of beat and strength of contraction? Why?
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.
What is an intrinsic control mechanism?
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
How does sarcomere lengths affect the strength of contraction?
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+
What is the rate staircase?
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
What are the intrinsic control mechanisms of the heart rate and contraction?
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
What is the mechanism of the frank-starling law?
Due to the shorter titin in myofibrils
What are the types of extrinsic control mechanisms?
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
What is the effect of potassium on the Action potential?
It makes the action potential shorter
Decreases strength of contraction
What are the effects of catecholamine?
Binds to beta receptor
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
What are the effects of Cyclic AMP?
Increases Ca entry from ECM to increase strength of contraction
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
What is phospholamban?
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
How do catecholamines decrease twitch duration?
1. increased SR reuptake of Ca
2. Changes in affinity of troponin for Ca (phosphorylation of troponin I) allow Ca to dissociate faster
What is heart failure?
The inability of the heart to supply sufficient blood flow to meet the body’s needs
Common causes include:
iii. valvular heart disease
What are potential mechanisms for heart failure?
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