Cardiac Contraction Flashcards
Describe Cardiomyocyte structure (length, myocytes, t-tubules, cytoplasm and sacromeres)
- Cardiomyocytes 60–140 μm in length and 17–25 μm diameter make up the branching myofibres. Each myocyte contains multiple, rod-like cross-banded 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).
GIve an overview of Cardiomyocyte function (4)
- The T tubules (invaginations of the membrane) have calcium channels and ensure calcium is delivered deep into the cell close to the sarcomere.
- Ca2+ enters via calcium channel that open in response to the wave of depolarization 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 an Na+/Ca2+ exchanger.
How does electrical excitability contract cardiac myocytes?
- Contraction is determined by INCREASE in [Ca2+]i
- Higher increases in Ca2+ → increased force of contraction
- Intracellular Ca2+ levels increase from 0.1 µM to about 10 µM
INTRACELLULAR EVENTS
- Diastolic [Ca2+]I ̴ 0.1 μM
- Normal systole [Ca2+]i may rise ̴ 1 μM
- Maximum systole [Ca2+]i may rise ̴10 μM
- Cell shortening usually less than maximum
- CICR = Ca induced Ca release
Describe Intra-cellular rise in [Ca2+]i events
- Action potential (Na+ ions) depolarises T-tubules & activates VGCCs causing Ca2+ influx
- Ca2+ binds to RyR located on SR - close association with T-tubules
- Release of Ca2+ from SR - Ca induced Ca release (CICR)
- Ca2+ to troponin, displacement of tropomyosin/troponin complex, exposing active sites on actin
- Myosin thick filament heads bind to active sites
- Myosin head ATPase activity release energy (ATP to ADP) slides filaments
Describe how calcium causes contraction
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What does troponin do, and describe the subunits of troponin
• 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+
What happens when calcium binds to troponin and what are TnT and TnI also involved in?
- Binding of Ca2+ to TnC leads to conformation changes of tropomyosin and exposure of actin binding sites.
- TnI and TnT are important blood plasma markers for cardiac cell death eg. following MI
What happens when you have a decrease in [Ca2+]I and relaxation (6)
- Action potential repolarisation (K+ ions influx) repolarises T-tubules – closure of VGCCs, and Ca2+ influx.
- No Ca2+ influx, no CICR.
- Extrusion of Ca2+ from cell (30%)- by Na+/Ca2+ exchanger (NCX).
- 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).
- Uptake of Ca2+ in mitochondria.
- Reduction in [Ca2+]i, myosin / actin binding reduced, preventing contraction – chambers relaxed and can refill.
Describe the difference between starlings law and contractility.
Describe the graph
Starlings law and calcium ions both affect contractility. If we stretch the heart we have more places for the calcium to bind, and more places for troponin to bind so we get stronger contraction when we stretch the heart. This shows at different levels of calcium we get different curves. Stroke volume against stretch.
Describe how drugs can be used to treat heart failure
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 1-adrenoceptors to increase contractility by phosphorylating calcium channels.
Describe what happens when noradrenaline binds at an alpha 1 adrenoreceptor
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What does activation of PKA lead to? (4)
- Increased Ca2+ channel so higher Ca2+ levels and greater contraction
- Increased K+ channel opening so faster repolarisation and shorter action potential…leads to faster heart rate
- Increased sarcoplasmic reticulum Ca2+ATPase, so uptake of Ca2+ into storage by SR allowing faster relaxation
- Overall stronger faster contractions but same diastolic time to allow for filling with blood & coronary perfusion.
Give an example of a cardiac glycoside and describe brief details about it
- 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
What is the mechanism of action of digoxin? (5)
- Digoxin inhibits Na+/K+ ATPase.
- Build up of [Na+]I lowers concentration gradient. (which normally powers Na/Ca exchanger).
- Less Ca2+ extrusion by Na/Ca exchanger.
- More Ca2+ uptake into stores and greater CICR.
- Digoxin blocks channel, leaving calcium inside the cell.
Describe other inotropic agents
• Dobutamine & dopamine are 1-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 β-blockers.
• Amrinone – a phosphodiesterase inhibitor
Type III phosphodiesterase (PDE3) is heart specific and converts cAMP into AMP
This reduces cAMP and decreases PKA activity – which reduces contractility.
Phosphodiesterase inhibition leads to a build up of cAMP that activates PKA to phosphorylate VGCCs and Ca2+ influx. Only used in severe cases eg. those waiting for heart transplants
