Cardiac Contraction Flashcards
How does electrical excitability contract cardiac myocytes?
Electrical excitability stimulates VGCCs to cause an [Ca2+] influx.
Cardiac contraction is determined by an increase in [Ca2+]i. Higher increases in Ca2+ concentration lead to an increased force of contraction.
RECAP: Describe how depolarisation can lead to contraction of the myocyte (molecularly).
1) An action potential (due to an influx of Na+ ions) depolarises the T-tubules & activates VGCCs, causing a Ca2+ influx
2) The Ca2+ binds to RyR located on sarcoplasmic reticulum (which are in close association with T-tubules)
3) There is the release of Ca2+ from sarcoplasmic reticulum, thanks to calcium-induced calcium release (CICR)
4) Ca2+ binds to troponin, displacing the tropomyosin/troponin complex, exposing active sites on actin
5) The myosin thick filament heads bind to the exposed active sites
6) Myosin head ATPase activity releases energy (ATP to ADP), which slides the filaments (ie. contraction)
Describe Troponin and its subunits.
Troponin regulates the conformation of Tropomyosin and is composed of 3 regulatory subunits:
- Troponin C (TnC) – binds Ca2+
- Troponin T (TnT) - binds to tropomyosin
- Troponin I (TnI) – binds to actin filaments
The binding of Ca2+ to TnC leads to the conformational changes of tropomyosin and the exposure of actin binding sites,
while TnI and TnT are important blood plasma markers for cardiac cell death (for eg. following a myocardial infarction).
Describe how the cell relaxes by decreasing the [Ca2+].
1) An action potential repolarisation (by the influx of K+ ions) repolarises T-tubules, leading to the closure of VGCCs, and a decrease of Ca2+ influx.
2) With no Ca2+ influx, there is no CICR.
3) There is the extrusion of Ca2+ from the cell (30%) by Na+/Ca2+ exchanger (NCX).
4) There is also Ca2+ uptake into sarcoplasmic reticulum via the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA, 70%) on the SR membrane, responsible for retrieving Ca2+ in the SR for next contraction (this requires energy in the form of ATP).
5) Lastly, there is also uptake of Ca2+ into the mitochondria.
Describe drugs that are used to increase contractility.
In the clinic, drugs are used to increase contractility - mostly to correct acute or chronic heat failure.
In general, these drugs increase the calcium ion concentration by:
1) increasing the VGCC activity (sympathetic memetic)
2) reducing Ca2+ extrusion (cardiac glycosides)
These are positive inotropes. They increase the energy or strength of contraction.
Sympathetic stimulation can have multiple actions on the heart. Describe some of them.
- increased Ca levels due to increased channels opened so greater contraction
- increased K+ channels so after repolarization and shorter action potential - faster HR
- Increased Sarcoplasmic reticulum Ca2+ ATPase - faster relaxation as faster uptake
- strong faster contraction but same diastolic time to allow for filing of blood and coronary perfusion
Noradrenaline acts on Beat -1 adrenoreceptors to increase contractility by phosphorylating calcium channels
Describe cardiac glycosides.
They have a positive inotropic effect on the heart, they are therefore called inotropes.
An example would be Digoxin, which increases the contractility of the heart. It is used for chronic heart failure. However, it is not used as much now, due to its side effects that are difficult to manage.
Digoxin’s mechanisms of action:
1) it inhibits Na+/K+ ATPase
2) this leads to a build of of intracellular Na+
3) this then leads to less Ca2+ extrusion via the Na+/Ca2+ exchanger
4) this means that there is more Ca2+ uptake into the stores, and thus there is greater CICR
Besides Digoxin, list other examples of inotropic agents.
- DOBUTAMINE and DOPAMINE: β1 adrenoceptor stimulants
- GLUCAGON: acts at G-protein coupled receptor ligand
- AMRINONE: a phosphodiesterase inhibitor (so preventing the inactivation of cAMP)
What do different levels of calcium mean in terms of Starling’s Law?
Different levels means different Starling curves
How does a rise in Ca2+ initiate contraction?
- Calcium binds to Troponin C exposing actin binding sites
- Hydrolysis of ATP causes mysoin to extend and bind head to actin forming cross bridges
- Power stroke moves actin filament relative to myosin. ADP + Pi released from the myosin head
- Myosin remains attached until a new molecule of ATP binds. Myosin cocked back ready to make further cross links
- Cycle continues until cellular levels of Ca decrease allowing Ca to dissociate from Troponin which return to original conformation which blocks actin binding site
