Cardiac contraction Flashcards
Explain the structure of cardiomyocytes
Cardiomyocytes:
60-140 um in length and 17-25 um in diameter.
-each myocyte contains multiple, rod like cross banded strands (myofibrils) that run the length of the cell and are composed of repeating sacromeres.
Explain the structure of T tubules
T tubules are invaginations of the muscle cell membrane (sacrolemma) that penetrate the centre of cardiac muscle cells.
Explain the structure of the cytoplasm between the myofibrils
Cytoplasm between the myofibrils contains the single centrally located nucleus, mitochondria, and the sarcoplasmic reticulum (intra cellular membrane system)
Explain the sacromeres structure
-sacromeres causes muscle contraction when their component actin and myosin filaments move relative to eachother.
-the varying actin myosin overlap is shown for systole (contraction) and diastole (relaxation)
Give an overview of cardiomyocytes function
-the T tubules have calcium channels to ensure calcium delivery to the cell close to the sacromeres.
-Ca2+ enters via calcium channels that open in response to a wave of depolarisation that travels across the sarcoemma.
-this triggers the release of more calcium ions 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+ leaves the cell through an Na+/Ca2+ exchanger
How does electrical excitability contract cardiac myocytes
Contraction is determined by an increase in Ca2+. Higher increases in Ca2+ causes an increased force of contraction.
-Action potential causes cell depolarisation which opens calcium channels.
Ex-plain the steps in the intra cellular rise in calcium
1) Action potential (Na+ ions) depolarises T-tubules and activates VGCCs (voltage gated calcium channels). This causes a Ca2+ influx.
2) Ca2+ binds to RyR located on sarcoplasmic reticulum- which has close association with T-tubules.
3) Release of Ca2+ from SR- Ca2+ induced Ca2+ release (CICR)
4) Ca2+ binds to troponin, displacement of tropomyosin/troponin complex, exposes active site on actin
5) Myosin thick filament heads bind to active sites on actin and filaments slide (using ATP)
List the 3 sub units of troponin and what they bind to
Troponin regulates conformation of tropomyosin and is composed of 3 regulatory subunits:
1) Troponin T (binds to tropomyosin)
2) Troponin I (binds to actin filaments)
3) Troponin C (binds to Ca2+)
Explain the process of decrease in calcium and relaxation
1) Action potential repolarisation (K-) ions leave and repolarises the T-tubules. This causes closure of VGCCs and less Ca2+ influx.
2) No Ca2+ influx leads to no CICR.
3) Extrusion of Ca2+ from the cell via the Na+/ Ca2+ exchanger.
4) Ca2+ uptake into sarcoplasmic reticulum via SR membrane through Ca2+ + ATPase
5) Ca2+ in SR for next contraction, even relaxation requires ATP
What is the difference between starling’s law and contractility (inotropy)
How does the sympathetic nervous system control cardiac contractility
Noradrenaline acts via the a1- adrenoreceptors, this increases contractility by phosphorylating Ca2+ channels. This allows greater Ca2+ influx and higher intra cellular levels
Explain how clinical situations can control cardiac contractility
Drugs are sometimes needed to increase contractility, mostly this is to correct acute or chronic heart failure
How do these drugs increase intra cellular calcium?
These drugs increase intracellular calcium by:
1) Increasing voltage gated calcium channel activity
2) Reducing Ca2+ extrusion (cardiac glycolysis)
What are drugs referred to?
Drugs are positive INOTROPES (substance altering energy of muscle contraction)
How do B1- adrenoceptors induce increased contractility
1) B1-adrenoceptors are found in the contractile cells of the heart, atrial and ventricular walls.
2) Phosphorylation of the voltage gated calcium channel increases activity
3) Increased Ca2+ influx during plateau phase
What will an increased protein kinase A concentration lead to?
Increased protein kinase A (PKA) leads to:
1) Increased Ca2+ channel so higher Ca2+ levels and greater contraction
2) Increased sarcoplasmic reticulum by using Ca2+ATPASE. Uptake of Ca2+ into storage by SR which allows 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 and coronary perfusion.
Explain the the use of Digoxin
Digoxin increases contractility by reducing Ca2+ extrusion (expelling)
-used for chronic heart failure
-not used now due to side effects
Explain the mechanism of action of Digoxin
1) Digoxin inhibits Na+/K+ ATPASE
2) Build up of intracellular Na+ lowers concentration gradient
3) Less Ca2+ expulsion by Na+/ Ca2+ exchanger
4) More Ca2+ uptake into stores and greater CICR
Explain the side effects of Digoxin
1) Unusual tiredness and fatigue
2) anxiety
3) Hallucinations
4) Visual disturbances
5) Nausea
List some other inotropic agents
1) Dobutamine and dopamine are both a1-adrenoceptor stimulants and may be used in acute heart failure
2) glucagon- acts as a GPCR, stimulates GS pathway, increases cAMP and PKA activity
3) Amrinone- a phosphodiesterase inhibitor
4) PDE3 converts cAMP into AMP, reduces cAMP and decreases PKA activity.
Explain what happens when there is a inhibition by Amrinone
Inhibition by Amrinone leads to a build up of cAMP causing increased activation of PKA which phosphorylates Ca2+ channels + increases Ca2+ influx
