Cardiac Contraction

Question 1

Describe cardiomyocyte structure

Answer 1

Cardiomyocytes 60-140um in length and 17-25um diameter make up the branching myofibers
Each myocyte contains multiple, rod-like cross-branded strands (myofibrils) that run the length of the cell and are composed of repeating sarcomeres
T tubules are invaginations of the muscle cell membrane (sarcolemma) that penetrate into the centre of cardiac muscle cells
Cytoplasm between the myofibrils contains the single centrally located nucleus, mitochondria, and sarcoplasmic reticulum (intracellular membrane system)
Sarcomeres cause muscle contraction when their component actin and myosin filaments move relative to each other
The varying actin myosin overlap. Is shown for systole (contraction) and diastole (relaxation)

Question 2

How does Ca2+ influence cardiac myocytes?

Answer 2

The T tubules have calcium channels and ensure calcium is delivered deep into the cell close to the sarcomere
Ca2+ enters via calcium channel that opens in response to the wave of depolarisation that travels along the sarcolemma where they trigger the release of more calcium from the sarcoplasmic reticulum and initiate contraction
The varying actin-myosin overlap is shown for systole, when [Ca2+]is maximal and diastole when [Ca2+] is minimal
Eventually, the Ca2+ that has entered the cell leaves predominantly through a Na+/Ca2+ exchanger

Question 3

How does cardiac myocyte contraction start (voltage-wise)

Answer 3

Depolarisation wave sweeps through the heart.

As it reaches each cell it is enough to reach the threshold for Na+ channel opening.

Question 4

How does electrical excitability contract cardiac myocytes?

Answer 4

Contraction is determines by increase in [Ca2+]i
Higher increase in Ca2+ → increased force of contraction
Intracellular Ca2+ levels increase 0.1uM to about 10uM

Question 5

How does an increase in intracellular calcium ion concentration cause contraction?

Answer 5

1. Action potential (Na+ ions) depolarises T-tubules and activates voltage gated calcium channels causing Ca2+ influx
   
   2. Ca2+ binds to RyR located on SR- close association with T-tubules
   3. Release of Ca2+ from SR- Ca induced Ca release CICR
   4. Ca2+ binds to troponin, displacement of tropomyosin/troponin complex, exposing active sites on actin
   5. Myosin thick filament heads bind to active sites on actin and filaments slide (using ATP)

Question 6

How do actin and myosin contract?

Answer 6

1. Calcium binds to troponin C which changes conformation of tropomyosin exposing actin-binding sites
2. Hydrolysis of ATP causes myosin to extend and bind head to actin forming cross-bridges
3. Power stroke moves actin filament relative to myosin. ADP + Pi released from the myosin heads
4. Myosin remains attached to actin until a new molecule of ATP binds
5. CYcle continues until cellular calcium levels decrease allowing calcium to dissociate from troponin which returns to original conformation which blocks the actin-binding site

Question 7

What are the different subunits of troponin?

Answer 7

Troponin regulates conformation of tropomyosin and is composed of 3 regulatory subunits
Troponin T (Tn T) binds to tropomyosin
Troponin I (Tn I) binds to actin filaments
Troponin C (Tn C) binds Ca2+
Binding of Ca2+ to Tn C leads to conformation changes of tropomyosin and exposure of actin-binding sites
Tn I and Tn T are important blood plasma markers for cardiac cell death e.g. following MI

Question 8

How does [Cai] decrease and muscle relax?

Answer 8

1. Action potential repolarisation (K+ ions leave) repolarises T-tubules- closure of VGCCs, ↓ Ca2+ influx
   
   2. No Ca2+ influx, no CICR
   3. Extrusion of Ca2+ from cell (30%)- by Na+/Ca2+ exchanger (NCX)
   4. Ca2+ uptake into SR via SR membrane Ca2+ATPase (sarco/endoplasmic reticulum ATPase- SERCA, 70%) Ca2+ in SR for next contraction, even relaxation requires energy (ATP)
   5. Uptake of Ca2+ in mitochondria
      Reduction in [Ca2+]i, myosin/actin binding reduced, preventing contraction- chambers relaxed and can refill

Question 9

How is cardiac contractility controlled clinically?

Answer 9

In the clinic drugs are sometimes needed to increase contractility of the heart; mostly to correct acute or chronic heart failure
In general these drugs increase [Ca2+]i
1. Increasing VGCC activity (sympathetic mimetic)
2. Reducing Ca2+ extrusion (cardiac glycosides)
These are positive inotropes
Increase energy/strength of contraction
Sympathetic nervous system:
Noradrenaline (NA) acts on b1-adrenoceptors to increase contractility by phosphorylating calcium channels.

Question 10

What do beta1 adrenoceptors do?

Answer 10

b1-Adrenoceptors induce increased contractility
B1 adrenergic receptors are found on the contractile cells of the heart, the atrial and ventricular cells
more info

Question 11

What does an increase in protein kinase A (PKA) lead to?

Answer 11

1. Increased Ca2+channel so higher Ca2+ levels and greater contraction
   
   2. Increased K+ channel opening so faster repolarisation and shorter action potential which leads to faster heart rate
   3. Increased sarcoplasmic reticulum Ca2+ATPase, so uptake of Ca2+ into storage by SR allowing faster relaxation
   4. Overall stronger faster contractions but same diastolic time to allow for filling with blood and coronary perfusion

Question 12

What are cardiac glycosidases and what is their mechanism of action?

Answer 12

Positive inotropic action of the heart and are therefore called inotropes
Digoxin increases contractility by reducing Ca2+ extrusion
Used for chronic heart failure
Not used so much now due to side effects
Mechanism of action:
1. Digoxin inhibits Na+/K+ ATPase
2. Build up of [Na+]I lowers concentration gradient (which normally powers Na+/Ca2+ exchanger)
3. Less Ca2+ expulsion by Na+/Ca2+ exchanger
4. More Ca2+ uptake into stores and greater CICR

Question 13

Try to name some other inotropic agents

Answer 13

Dobutamine and dopamine are b1-adrenoceptor stimulants- may be used in acute heart failure
Glucagon- acts at G protein-coupled receptor, stimulates Gs pathway, increases cAMP and PKA activity.
Used in patients with acute heart failure who are taking b-blockers
Amrinone- a phosphodiesterase inhibitor
Type III phosphodiesterase (PDE3) is heart-specific and converts cAMP into AMP which normally reduces cAMP and decreases PKA activity- thereby limiting contractility
Inhibition of Amrinone leads to a build-up of cAMP that activates PKA to phosphorylate VGCCs and ↑Ca+ influx
Only used in severe cases e.g. those waiting for heart transplants.