Cardiac Contraction

Question 1

What is a myocyte?

Answer 1

A myocyte (also known as a muscle cell) is the type of cell found in muscle tissue.

Question 2

How does electrical excitability contract cardiac myocytes?

Answer 2

• Electrical excitability stimulates voltage gated calcium ion channels (VGCCs) to cause an [Ca2+] influx.
• Cardiac contraction is determined by an increase in [Ca2+]_i.
• Higher increases in Ca2+ concentration lead to an increased force of contraction.

Question 3

Describe how depolarisation can lead to contraction of the myocyte (molecularly).

Answer 3

1. An action potential (due to an influx of Na+ ions) depolarises the T-tubules & activates VGCCs, causing a Ca2+ influx.
2. The Ca2+ binds to ryanodine receptors (RyR) located on sarcoplasmic reticulum (which are in close association with T-tubules).
3. This causes the release of Ca2+ from sarcoplasmic reticulum, due to calcium-induced calcium release (CICR).
4. The Ca2+ binds to troponin causing it to change shape.
5. This pulls the tropomyosin away from the actin-myosin binding site on the actin filament.
6. Now that the binding site has been exposed the myosin head binds to the actin filament forming an actin-myosin cross bridge.
7. Myosin head ATPase activity releases energy (ATP to ADP), which slides the filaments (ie. contraction).

Extra info:-

1. (Once attached to the actin filament the myosin head flexes, pulling the actin filament along. The molecule of ADP bound to the myosin head is released. An ATP molecule can now bind to the myosin head. This causes the head to detach from the actin filament.
2. The calcium ion present in the sarcoplasm also activate the ATPase activity of the myosin. This hydrolyses the ATP to ADP and phosphate, releasing energy which the myosin head uses to return back to its original position.
3. The myosin head can now attach itself to another actin-myosin binding site further along the actin filament and the cycle is repeated.)

Question 4

Describe Troponin and its subunits.

Answer 4

• Troponin regulates the conformation of Tropomyosin and is composed of 3 regulatory subunits: -
  
  • Troponin C (TnC) - binds Ca2+.
  • Troponin T (TnT) - binds to tropomyosin.
  • Troponin I (TnI) - binds to actin filaments.
• The binding of Ca2+ to TnC leads to the conformational changes of tropomyosin and the exposure of actin binding sites.
• TnI and TnT are important blood plasma markers for cardiac cell death (for eg. following a myocardial infarction) as they are released in the blood stream and can be measured a few hours later.

Infarction meaning - obstruction of the blood supply to an organ or region of tissue, typically by a thrombus or embolus, causing local death of the tissue.

Question 5

Describe how the cell relaxes by decreasing the [Ca2+].

Answer 5

1. During an action potential repolarisation (by the influx of K+ ions) the T-tubules are repolarised, leading to the closure of VGCCs, and a decrease of Ca2+ influx.
2. With no Ca2+ influx, there is no CICR.
3. There is an extrusion of Ca2+ from the cell (30%) by Na+/Ca2+ exchanger (NCX). Sodium comes in and calcium goes out.
4. There is also Ca2+ uptake into sarcoplasmic reticulum via the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA, 70%) on the SR membrane, responsible for retrieving Ca2+ in the SR for next contraction (this requires energy in the form of ATP).
5. Lastly, there is also uptake of Ca2+ into the mitochondria.

The reduction in [Ca²⁺]_i causes less actin / myosin binding which prevents contraction and the heart chambers can relaxed and refil.

Extrusion meaning - to force out.

Question 6

What effect does contractility [Ca2+]_i have on Starling’s law? (Inotropy)

Answer 6

• Starling’s law states that if we stretch a muscle it will contract harder.
• The reason for starling’s law is that when we stretch a muscle we allow a few more bindin sties between actin and myosin.
• We also allow Ca2+ to get into them so we get harder contractions.
• As we increase the [Ca2+] the contractions get even harder so you get a series of Starling’s curve.
• At low levels of Ca2+ the starling’s curve is lower and as you increase the intracellular levels of calcium you still get a starling’s curve but with a higher stroke volume.
• There are two levels of control that will work togther to moderate the strength of the heart beat.
  
  • Extrinsic control - which is the amount of calcium that will make your heart pump harder.
  • Intrinsic stretch - It causes an increased stretch leading to an increased end diastolic volume.

Inotropy meaning - the force of muscle contraction.

Extrinsic meaning - it means not essential activity.

Intrinsic meaning - It means an essential activity.

Question 7

What is the importance of Starling’s law?

Answer 7

• Due to the intrinsic property of myocardium that is responsible for the Starling mechanism, the heart can automatically accommodate an increase in venous return (blood from the body to heart), at any heart rate.
• The mechanism is of functional importance because it serves to adapt left ventricular output to right ventricular output.
• If this mechanism did not exist and the right and left cardiac outputs were not equivalent, blood would accumulate in the pulmonary circulation (were the right ventricle producing more output than the left) or the systemic circulation (were the left ventricle producing more output than the right).

Question 8

Describe drugs that are used to increase contractility.

Answer 8

• In the clinic, drugs are used to increase contractility - mostly to correct acute or chronic heart failure.
• In general, these drugs increase the calcium ion concentration by:-
  
  1. Increasing the VGCC activity (sympathetic memetic).
  2. Reducing Ca2+ extrusion (cardiac glycosides).
• These are positive inotropes. They increase the energy or strength of contraction.
• This is possible by the sympathetic nervous system that stimuates noradrenaline (NA) to act on β₁ adrenoceptors to increase contractability.

Inotrope meaning - An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

Question 9

How does β₁ adrenoceptors induce increased contractility?

Answer 9

1. The β₁ adrenoceptor is a G protein (that has 7 transmembrane domains).
2. Noradrenaline binds to it actvating the G​_αS subunit which activates adenylyl cyclase.
3. Adenylyl cyclase removes a couple of phosphates from ATP to form cAMP. cAMP activates protein kinase A.
4. Protein kinase A adds a phosphate to the voltage gated calcium channel making it more easy to open.
5. The levels of intracellular calcium increases and this results in calcium induced calcium release (CICR).
6. This further increases the levels of calcium and allowing actin - myosin cross bridges to form resulting in increased contractility.

Question 10

Sympathetic stimulation can have multiple actions on the heart. Describe some of them.

Answer 10

• Adding a β₁ adrenoceptor causes the calcium channels to become more sensitive so we get a much bigger influx of calcium (positive inotropy). This causes strong depolarisation (as calcium is positively charged).
• At the same time the channel opens and closes faster so we get a shorter but bigger plateau.
• There is also an increased heart rate and conduction (positive chronotropy).
• The relaxation period stays relatively similar, which is important as we need to heart to relax so that the cardiac circulation can occur. This means that we must not leave too much Ca2+ in the cell after contraction.

Chronotropy meaning - Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the nerves that influence it, such as by changing the rhythm produced by the sinoatrial node. Positive chronotropes increase heart rate; negative chronotropes decrease heart rate.

Question 11

Describe cardiac glycosides.

Answer 11

• They have a positive inotropic effect on the heart, they are therefore called inotropes.
• An example would be Digoxin, which increases the contractility of the heart by reducing Ca2+ extrusion.
• It is used for chronic heart failure.
• However, it is not used as much now, due to its side effects that are difficult to manage.
• Digoxin’s mechanisms of action:-
  
  1. It inhibits Na+/K+ ATPase. This ion transport system moves Na+ out of the cell and brings K+ ions into the cell.
  2. This leads to a build of of intracellular Na+.
  3. There is then less Ca2+ extrusion via the Na+/Ca2+ exchanger.
  4. This means that there is more Ca2+ uptake into the stores, and thus there is greater CICR.

Question 12

Besides Digoxin, list other examples of inotropic agents.

Answer 12

1. DOBUTAMINE and DOPAMINE:
   
   • They are drugs that bind to the β1 adrenoceptor stimulants.
   • They may be used in acute heart failure.
2. GLUCAGON:
   
   • Acts at G-protein coupled receptor, that stimulates the Gs pathway, increasing cAMP and PKA activity.
   • It is used in patients that are taking β-blockers.
3. AMRINONE:
   
   • It is a phosphodiesterase (PDE) inhibitor.
   • Phosphodiesterase converts cAMP into AMP, thus reducing cAMP and decreasing PKA activity.
   • This reduces contractility.
   • The heart has type III phosphodiesterase.
   • PDE inhibition leads to a build up of cAMP that activates PKA to phosphorylate VGCCs and to increase Ca2+ influx.
   • It is only used in severe cases. E.g. those waiting for a heart transplant.