Heart 3 contractility

Question 1

What is the idea of excitation-contraction coupling?

Answer 1

There is depolarisation due to Na+ influx, activation of L-type voltage activated calcium channels and an influx of extracellular calcium. There is activation of ryanodine receptors (RyR2) on the sarcoplasmic reticulum, and Ca2+ induced Ca2+ release. There is Ca2+ influx via the reverse mode of the Na+-Ca2+ exchanger.

Question 2

What is the function of the calcium released by the sarcoplasmic reticulum due to the opening of the ryanodine receptor?

Answer 2

This binds to the troponin C of the troponin-tropomyosin complex on the actin filaments in sarcomeres which facilitates the formation of cross-bridges between actin and myosin and myocardial contraction.

Question 3

What are the features of the ryanodine receptor?

Answer 3

It is a large homotetrameric protein complex that causes intracellular calcium release on the sarcoplasmic reticulum.

Question 4

What are the three main isoforms of the ryanodine receptor and where are they found?

Answer 4

RyR1 - skeletal muscles, RyR2 - cardiac muscles and RyR3 - brain and other tissues.

Question 5

How does arrangement of ryanodine receptors vary in skeletal and cardiac muscles?

Answer 5

In skeletal muscles they are physically arranged in tetrads, whereas in cardiac muscles they are arranged in loose clusters.

Question 6

What are the steps involved in calcium induced calcium release in the cardiac myocyte?

Answer 6

Ca enters via an L-type voltage activated calcium channel which activates clusters of RyRs. There is local calcium release (calcium spark) and rapid summation of local events. This causes a global raise in calcium (calcium wave), ending in contraction.

Question 7

What does the N terminus of the RyR2 receptor contain?

Answer 7

Calcium binding sites, phosphorylation sites for PKA, CaMKII, PKG, binding sites for phosphatases, calmodulin binding site and magensium binding sites.

Question 8

What binds to each subunit of the RyR2 receptor in order to stabilise it?

Answer 8

Calstabin2 - binds in a closed state.

Question 9

What is the effect of ryanodine on its receptor?

Answer 9

It is an activator at low concentrations and an inhibitor at high concentrations, due to the presence of a lower affinity binding site that is only bound in high concentrations.

Question 10

What drugs have an effect on the ryanodine receptor?

Answer 10

Caffeine - low concentrations increase the sensitivity of the receptor to calcium, whereas high concentrations can activate the receptor leading to rapid calcium release. Immunophilins also bind FKBP such as FK506 and rapamycin.

Question 11

How can drugs make the ryanodine receptor more leaky?

Answer 11

They displace calstabin from its binding site at the ryanodine receptor.

Question 12

What is the purpose of calstabin on the ryanodine receptor?

Answer 12

It keeps the channel in a closed state and maintains the channel being closed in these conditions.

Question 13

What are the mechanisms of calcium removal in the cardiac myocyte?

Answer 13

Reuptake into the sarcoplasmic reticulum by SERCA, extrusion by the Na+Ca2+ exchanger, uptake by mitochondrial Ca2+ uniporter and extrusion by sarcolemmal Ca2+ ATPase.

Question 14

What is the most used method of calcium removal in the cardiac myocyte?

Answer 14

Reuptake into the SR (70-80%), extrusion by the Na+/Ca2+ exchanger (20-30%), and the other two effects are very minimal.

Question 15

What does SERCA stand for?

Answer 15

Sarcoplasmic/endoplasmic calcium ATPase.

Question 16

How is SERCA activated?

Answer 16

An increase in cytosolic calcium.

Question 17

What is a regulator of SERCA?

Answer 17

Phospholamban.

Question 18

What is the mechanism of phospholamban?

Answer 18

In its unphosphorylated state, it is an inhibitor of SERCA. Once phosphorylated, there is faster uptake of calcium into the sarcoplasmic reticulum.

Question 19

What are the two ways in which phospholamban can be phosphorylated?

Answer 19

PKA and CaMKII.

Question 20

What is NCX?

Answer 20

The sodium calcium exchanger.

Question 21

What is activity of NCX driven by?

Answer 21

An increased cytosolic concentration of calcium or sodium.

Question 22

What is the ratio of calcium and sodium that is exchanged in the NCX transporter?

Answer 22

1 calcium is exchanged for 3 sodium - it is electrogenic.

Question 23

What does electrogenic mean?

Answer 23

There is a change in electrical potential of a cell.

Question 24

What is the forward mode of the NCX?

Answer 24

It is activated by increased cytosolic calcium and removes 1 calcium in exchange for 3 sodium. This reduces the calcium concentration.

Question 25

What is the reverse mode of the NCX?

Answer 25

It is activated by increased cytosolic Na+ and expels 3Na for 1Ca and increases the cytosolic calcium concentration.

Question 26

What is the reverse mode of the NCX important in?

Answer 26

Inotropic action of digoxin.

Question 27

What are the three processes in the heart that cause increased contraction?

Answer 27

Phosphorylation of L type calcium channels to increase activity, phosphorylation of ryanodine receptors and a stimulatory effect - phosphorylation of troponin I to cause increased calcium sensitivity.

Question 28

What effect do catecholamines have on the heart?

Answer 28

Increased Ca2+ via PKA-mediated phosphorylation causing and increase in Ca influx via L-VACC and increased calcium release via RyR2.

Question 29

What is inotropic and lusitropic effects?

Answer 29

Inotropic - contraction, lusitropic - contraction.

Question 30

What is the other effect of catecholamines on the heart?

Answer 30

Increase of Ca reuptake into the SR via PKA-mediated phosphorylation, causing increased activity of SERCA.

Question 31

What are some abnormalities in cardiac Ca2+ that can trigger tachyarrhythmias?

Answer 31

Mutation in RyR2/CASQ2 that can cause CVPT (which can lead to VF), increased Ca2+ overload by drugs or leaky RyRs can trigger DADs, or hyperphosphorylation and enhanced activity of Cav1.2 can promote EADs.

Question 32

What are some catecholamines that are positive inotropes?

Answer 32

Noradrenaline, adrenaline, dobutamine, isoprenaline.

Question 33

What are some cardiac glycosides?

Answer 33

Digoxin, digitoxin and ouabain.

Question 34

What is a calcium sensitiser?

Answer 34

Levosimendan.

Question 35

What is the source of production of digoxin?

Answer 35

Foxglove.

Question 36

What are the sugars on the structure of cardiac glycosides important in?

Answer 36

Solubility and binding.

Question 37

What are the steroid w/ lactone ring important for in cardiac glycosides?

Answer 37

Biological activity.

Question 38

What is the main cellular mechanism of cardiac glycosides?

Answer 38

Inhibition of the Na+/K+ ATPase by binding to an extracellular K+ binding site in a competitive manner.

Question 39

What is the function of cardiac glycosides?

Answer 39

Increase the cardiac output.

Question 40

What is the mechanism of digoxin as positive inotropic action?

Answer 40

They inhibit the Na/KATPase which causes sodium build up, this activates the reverse mode of the NCX and increases intracellular calcium. More calcium is stored in the SR and hence more is available for release. The force of contraction is therefore increased.

Question 41

What is the mechanism for digoxin cardiac toxicity and DAD?

Answer 41

There is a build up of calcium in the cytoplasm which will stimulate the forward mode of teh NCX (removing Ca2+). This has an electrogenic effect and more sodium in creates a positive charge in the cell. This causes membrane depolarisation and triggers a DAD that can cause arrhythmias.

Question 42

What is the mechanism of Levosimendan?

Answer 42

It binds to troponin C in a calcium dependent manner and prolongs its action.

Question 43

What are the cardiac benefits of Levosimendan?

Answer 43

It does not increase ATP consumption or cytosolic calcium. It can synergise with PKA-dependent phopshorylation of TnI and inhibits PDE3a, causing increased cAMp levels.

Question 44

What are some of the other benefits of Levosimendan?

Answer 44

It activates potassium ATP sensitive channels in blood vessels to cause vasodilation.