Cardiac Contraction Flashcards
Describe the structure of 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
Describe T tubules
Invaginations of the muscle cell membrane (sarcolemma) that penetrate the centre of cardiac muscle cells
What is found in the cytoplasm between myofibrils
Cytoplasm between myofibrils contain a single centrally located nucleus, mitochondria and sarcoplasmic reticulum
Describe 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)
What is the function of cardiomyocytes
- 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
Graph showing how intracellular calcium causes contraction
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
1) Action potential (Na+ ions) depolarises T-tubules & activates VGCCs causing Ca2+ influx
2) Ca2+ binds to ryanodine receptor located on sarcoplasmic reticulum (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 & filaments slide (using ATP)
Describe troponin and its different forms
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 TnC leads to conformational changes of tropomyosin and exposure of actin binding sites
TnI and TnT are important blood plasma markers for cardiac cell death eg. following MI
Describe how a decrease in intracellular Ca2+ and relaxation occurs
1) Action potential repolarisation (K+ ions leave) repolarises T-tubules – closure of VGCCs, and less Ca2+ influx
2) No Ca2+ influx, no CICR
3) Extrusion of Ca2+ from cell (30%) - by Na+/Ca2+ exchanger
4) Ca2+ uptake into sarcoplasmic reticulum (SR) via SR membrane Ca2+ATPase (around 70%) Ca2+ in SR for next contraction, even relaxation requires energy (ATP)
5) Uptake of Ca2+ in mitochondria
Reduction in calcium means myosin-actin binding is reduced, preventing contraction – chambers relax and can refill
Describe how a rise in intraceullular Ca2+ initiates contraction
1) Binding of myosin to actin. Inorganic phosphate is released
2) Power stroke as ADP released. Actin gets pulled towards the middle of the sarcomere
3) Rigor. Myosin in low energy form
4) New ATP binds to myosin head causing unbinding of myosin. Hydrolysis of ATP
5) Cocking of the myosin head. Myosin is now in the high energy form
Describe the decrease in Ca2+i and relaxation
1) Action potential repolarisation (K+ ions leave) repolarises T-tubules – closure of VGCCs, and less Ca2+ influx
2) No Ca2+ influx, no CICR
3) Extrusion of Ca2+ from cell (30%) - by Na+/Ca2+ exchanger
4) Ca2+ uptake into sarcoplasmic reticulum (SR) via SR membrane Ca2+ATPase (around 70%)
5) Ca2+ in SR for next contraction, even relaxation requires energy (ATP)
5) Uptake of Ca2+ in mitochondria
Reduction in calcium means myosin-actin binding is reduced, preventing contraction – chambers relax and can refill
Describe the difference between starling’s law & contractility
How can the sympathetic nervous system control cardiac contractility
Noradrenaline (NA) acts via beta 1 adrenoceptors to increase contractility by phosphorylating calcium channels and allowing greater Ca2+ influx and higher intracellular levels
How can cardiac contractility be controlled in clinical situations
Drugs are sometimes needed to increase contractility of the heart, mostly to correct acute or chronic heart failure
In general, these drugs increase intracellular calcium:
- Increasing voltage gated calcium channel activity (sympathetic mimetic)
- Reducing Ca2+ extrusion (cardiac glycosides)
These (sympathetic and clinical) are positive INOTROPES
Increase energy/strength of contraction
Describe in detail how beta 1 adrenoceptors induce contractility
- Beta 1 adrenergic receptors found on contractile cells of the heart (atrial and ventricular cells)
- Noradrenaline binds to the beta 1 receptor
- This activates a g protein that forms a G alpha s subunit
- This stimulates activity of adenylate cyclase causing formation of cAMP from ATP
- This then activated protein kinase A which allows for phosphorylation of a voltage gated calcium channel which increases its activity
- This leads to increased calcium influx and calcium induced calcium release
- The increased [Ca2+] allows interaction between myosin and actin to allow contraction
What does increased protein kinase A (PKA) lead to
1) Increased Ca2+ channel so higher Ca2+ levels and greater contraction
2) Increased sarcoplasmic reticulum Ca2+ATPase, so uptake of Ca2+ into storage by SR allowing faster relaxation
3) Increased K+ channel opening so faster repolarisation and shorter action potential, leads to faster heart rate
4) Overall stronger faster contractions but same diastolic time to allow for filling with blood & coronary perfusion
What are cardiac glycosides
- 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
Describe the glycosides’ mechanism of action
- Digoxin inhibits Na+/K+ ATPase.
- Build up of intracellular Na+ lowers concentration gradient (which normally powers Na+/Ca2+ exchanger).
- Less Ca2+ expulsion by Na+/Ca2+ exchanger.
- More Ca2+ uptake into stores and greater CICR.
State and describe some other inotropic agents that can impact heart contractility
Dobutamine & 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 β-blockers
Amrinone – a phosphodiesterase inhibitor
Type III phosphodiesterase (PDE3) is heart specific, and converts cAMP into AMP. This normally reduces cAMP and decreases PKA activity – thereby limiting contractility.
Inhibition by Amrinone leads to a build up of cAMP causing increased activation of PKA which phosphorylates Ca2+ channels and increases Ca2+ influx
It is usually only used in severe cases eg. those waiting for heart transplants
