S2: Heart - Contractility and Ionotropic Effect Flashcards
Compare electrical activity of the heart compared to amount of Ca2+ signalling in cells and cardiac myocytes length
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What is contraction determined by?
Contraction is determined by an increase in intracellular Ca2+ levels. The higher the increase in Ca2+. the greater the force of contraction.
Explain what happens to cause contraction in an atrial/ventricular myocyte
Phase 0 where membrane gets depolarised causing VGCC (L type) to open up and Ca2+ influxes into cell down steep conc gradient.
Phase 2 where there is sustained depolarisation of Ca2+ (slow to start and turn off).
This increases intracellular Ca2+ through calcium induced calcium release.
- Ca2+ going in activates the ryanodine receptor (ligand gated Ca2+ channel) found on the SR. Ca2+ diffuses out of the calcium store (CICR)
- This along with the calcium entering via the channel leads to a rise in intracellular calcium leading to contraction
Describe what happens with a rise in intracellular calcium at a sub-cellular level
Cardiac myocytes have T-tubules which are invaginations of the cell membrane that are adjacent with calcium channels, the SR and Z lines of the sarcomeres.
- The AP will run down the sarcolemma and go down and depolarise the T tubules. At the end of the T tubules there are VGNa channels which allow Na+ to enter (phase 0) and VGCC.
- Activation of VGCC when the membrane is depolarised and there is local Ca2+ influx. Small amounts of Ca2+ in sub-sarcolemic space binds to ryanodine receptors on SR. There is then Ca2+ release from SR (CICR)
- At rest, myosin-actin binding site is blocked by tropomyosin/troponin complex. Ca2+ binds to tropoin so there is displacement of the complex which exposes the active site for myosin head binding and cross bridge formation.
- Myosin thick filament heads bind to the active sites and ‘row’ the actin, the myosin head ATPase activity release energy (ATP to ADP) and detaches and cycle continues as myosin slides actin over it.
- This moves the actin and Z line towards sarcomere centre causign contraction.
What is the subsarcolemic space?
- Space between the T tubules and SR.
- Small space so not many Ca2+ ions need to be present to bind to ryanodine receptors
Why does greater rise in intracellular calcium concentration equal more contraction?
More Ca2+ means more actin-myosin binding sites are exposed due to more troponin/tropomyosin displaced. This means more crossbridges are formed hence greater force of contraction due to more rowing of actin and z lines.
What are the 3 regulatory subunits of troponin?
TnT - binds to tropomyosin
TnI - binds to actin filaments to hold tropomyosin in place
TnC - binds calcium
What troponin complex subunits act as blood plasma markers for cardiac cell death e.g. following MI?
TnI
TnT
Describe what happens with a decrease in intracellular calcium at a sub-cellular level
This stops contraction and relaxes the cardiac myocytes.
- AP downstroke (phase 3), during this phase there is K+ efflux
- This repolarises the T-tubules and there is closure of VGCC so a decrease in Ca2+ influx occurs. Eventually, there is no Ca2+ influx or CICR
Ca2+ still remains in the cell so this needs to be removed by extrusion or uptake into SR
- Extrusion is done by 3Na+/Ca2+ exchanger (NCX) found in plasma membrane
- Ca2+ uptake into SR via Ca2+ ATPase storing calcium for next contraction. This shows that energy is also needed for next contraction
- Uptake of Ca2+ into mitochondria
- A reduction in the [Ca2+]I means that there will be less free active sites so myosin heads can no longer bind to actin. Myosin head ATPase activity releases energy (ATP to ADP)
- Hence prevention of contraction mechanism and chambers are relaxed and can fill with blood
What is the difference between starlings law and contractility?
Contractility which is based on a rise in calcium is occurring at the same time as Starling’s law which is based on stretch only.
Describe a ventricular function curve/starling’s curve
What relationship does it show?
This shows the relationship between starlings law and contractility
Increasing end diastolic filling pressure (EDV) increases stroke volume. This is due to the increased intrinsic stretch of the cardiac myocytes (starlings law) leading to greater stroke volume.
However, if a point is chosen on the graph where EDV is kept constant, SV still increases via extrinsic control from sympathetic nervous activity on the heart. This will give a rise in Ca2+ causing greater contractility (ionotropy) which increases stroke volume.
This could be seen in exercise where filling pressure increases and then stays the same but stroke volume increases due to sympathetic activity/inotropy.
What are the two ways drugs usually do to increase intracellular calcium levels?
From a clinical perspective, drugs are mostly needed to increase contractility of the heart, mostly due to correct acute or chronic heart failure.
- Increasing VGCC activity (acting as a sympathetic mimetic)
- Reducing Ca2+ extrusion from cell (cardiac glycosides)
What are positive inotropes?
Drugs/Factors that increase the energy/strength of contraction
How do we increase SV/CO during e.g. excersize, haemorrhage?
By producing an ionotropic effect through stimulation of sympathetic nervous system (we can manipulate this through positive inotropes)
NA acts on b1-adrenoreceptors to increase contractility and hence stroke volume.
This occurs even if end diastolic pressure remains the same.
How does stimulation of b1 adrenoreceptors by NA cause an increase in contractility?
b1 is a GPCR. The Gas pathways is activated –> AC –> ATP to cAMP –> activates PKA
PKA phosphorylates VGCCs which causes them to be open for longer hence more Ca2+ influxes in the cell and there is CICR (from RyR receptors on SR). There is then greater intracellular concentration of Ca2+ thus more free binding sites on the sarcomeres and more crossbridge formation leading to increased contraction.
