4) Cardiac contraction

Question 1

What are cardiomyocytes?

Answer 1

• Cells that make up the myofibres.
• They contain many rod-like strands which are cross-banded (myofibrils) that run the length of the cell
• They are made of repeating sarcomeres

Question 2

What are T-tubules?

Answer 2

• Invaginations of the muscle cell membrane (sarcolemma) which penetrate into the centre of cardiac muscle cells.
• They have calcium channels which deliver Ca2+ close to the sarcomere

Question 3

Where is the cytoplasm located in a cardiomyocyte and what organelles does it contain?

Answer 3

• It is found in between the myofibrils
• It contains a single centrally located nucleus, mitochondria and sarcoplasmic reticulum (intracellular membrane system)

Question 4

What are sarcomeres?

Answer 4

• They cause muscle contraction when their actin and myosin filaments move relative to each other.
• The overlap of actin and myosin vary during systole (contraction) and diastole (relaxation)
• When systole occurs the actin and myosin overlap a lot
• When diastole occurs the actin and myosin overlap very little

Question 5

Describe the movement of Ca2+ in cardiomyocytes.

Answer 5

• Ca2+ enters via calcium channels which open due to a wave of depolarization (which travels along the sarcolemma)
• This triggers the release of more Ca2+ from the sarcoplasmic reticulum which initiates contraction
• When Ca2+ is maximal systole occurs
• When Ca2+ is minimal diastole occurs
• Eventually Ca2+ leaves the cell through a Na+/Ca2+ exchanger

Question 6

What controls the force of contraction in sarcomeres?

Answer 6

• The concentration of Ca2+ ions in the cell

- The higher the intracellular concentration of Ca2+ the stronger the contraction

Question 7

How does Calcium Induced Calcium Release (CICR) occur?

Answer 7

• First an action potential causes cell depolarisation resulting in voltage gated calcium channels to open.
• This causes an influx of calcium some of which bind to a Ryanodine receptor (RyR) on the sarcoplasmic reticulum (SR) causing calcium to be released from the SR (calcium stores).

Question 8

How does contraction occur?

Answer 8

• Ca2+ binds to troponin C which changes the conformation of the tropomyosin which exposes active sites on the actin
• Hydrolysis of ATP causes myosin heads to extend and bind to the active sites of actin forming cross bridges
• Power stroke occurs where the actin filaments are moved by the myosin. ADP and Pi are released from the myosin heads.
• The myosin remains bound to the actin until a new ATP binds to the myosin
• This cycle continues until intracellular calcium levels decrease allowing Ca2+ to be displaced from troponin which returns tropomyosin back to its original conformation

Question 9

What do the different subunits of troponin do?

Answer 9

• Troponin T (Tn T) binds to tropomyosin
• Troponin I (Tn I) binds to actin filaments
• Troponin C (Tn C) binds to Ca2+

(Tn I and Tn T are important blood plasma markers for cardiac cell death)

Question 10

How is the concentration of Ca2+ in cardiomyocytes decreased?

Answer 10

• Action potential and T-tubules repolarises as K+ leaves the cell causing voltage gated calcium channels to close which causes calcium influx to decrease and eventually stop
• As a result no CICR takes place
• Some Ca2+ extrusion occurs through the Ca2+/Na+ exchanger
• Some Ca2+ is taken up by SR via the membrane of the SR. This is done using a Ca2+ ATPase transporter. (This uses ATP which means relaxation also requires ATP)
• Ca2+ is taken up by the mitochondria as well

Question 11

What happens to stroke volume as Ca2+ increases?

Answer 11

• Stroke volume also increases

Question 12

How do drugs increase the contractility of the heart?

Answer 12

• In general they all increase the concentration of Ca2+
• Some increase the activity of voltage gated calcium channels (called sympathetic mimetics)
• Some reduce Ca2+ extrusion (called cardiac glycosides)
• These are positive inotropes as they increase energy/strength of contractions

Question 13

How does noradrenaline (NA) increase contractility of the heart?

Answer 13

• NA acts on B1-adrenoceptors (GPCRs) which triggers adenylate cyclase causing ATP to form cAMP.
• Increased cAMP activates protein Kinase A which phosphorylates calcium channels
• This allows them to open much more easily when there is an action potential.
• They open earlier and more of them open for longer so there is a much bigger Ca2+ influx
• The increased intracellular Ca2+ stimulates more CICR which has an increased effect on the actin/myosin filaments
• This increased effect leads to the increased contractility of the heart

Question 14

What are the effects of sympathetic stimulations on the heart?

Answer 14

• Increases activity of Ca2+ channels so greater Ca2+ influx and stronger contraction
• Increases K+ channel activity so faster repolarisation and shorter action potential leading to faster heart rate
• Increases SR Ca2+ ATPase activity so uptake of Ca2+ is quicker leading to faster relaxation
• Overall stronger force of contraction but same diastolic time to allow for filling with blood and coronary perfusion

Question 15

How does the cardiac glycosides (digoxin) work?

Answer 15

• Inhibits Na+/K+ pump
• This causes a build up of intracellular Na+, lowering the concentration gradient which normally powers the Na+/Ca2+ exchanger hence less expulsion of Ca2+ by the exchanger
• This means more Ca2+ uptake into stores and more CICR occurs