Cardiac contractility

Cardiac contraction

1. Stimulus - fast Na+ influx = rapid depol
2. Trigger - Ac. L-VACC + influc of extracellular Ca2+
3. Ac. of RyR2 on SR by Ca2+CICR

Ryanoid receptors

RyR1 = skeletal muscle

RyR2 = cardiac muscle

RyR3 = brain + other tissue

Intracellular Ca release channels

RyR1 structure

Skeletal muscles

Arranged into tetrads

4 channels associated with each RyR1

RyR2 structure

Cardiac muscles

Arranged in loose clusters

Ca2+ enter via L-VACC

Ac. cluster of RyRs

Local ca2+ rel. calcium spark

Rapid summation of local events

Global raise in Ca2+ = calcium wave

Contraction

RyRs pharmacology

2 binding sites

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High affinity binding site

Opens channel

Activated at low concentrations

Conc increases = channel shuts = act as inhibitor

Caffeine effect on RyRs

Low conc increases RyR sensitivity to calcium = channels open and our leaky

Arrhythmic effects

10mM = rapid Ca2+ rel

Immunosuppressants

Bind FKBP = keeps R closed at rest

Cause calcium overload

Cause PAC

PAC

premature atrial contraction

Triggered by immunophils/suppresants

Triggered by cardiac glycosides

CASQ2

Calsequestrin-2

Low affinity, high capacity for calcium

Unable to store in SR

Lead to CPVT

CPVT

catecholaminergic polymorphic ventricular tachycardia

Cardiac relaxation

1. calcium reuptake into SR by SECRA
2. Ca2+ extrusion by Na+-Ca2+ exchange
3. Calcium extrusion by Ca2+ATPase
4. Calcium uptake into mitochondria by mitochondrial CA2+ uniporter

SECRA

Sacroplasmic/endoplasmic reticulum calcium atpase

Step 1 relaxation

Calcium levels increase

Release phosphorylated phospholamban

Modifies and activates SECRA

Step 2 of relaxation - Forward mode

Activated by increase in cystolic calcium

Remove 1 calcium

Exchange for 3Na+

Decrease cytosolic calcium

Can cause membrane depolarisation = trigger DADs

Step 2 relaxation - Reverse phase

Activated by increase in cystolic Na+

Expel 3 Na+ in exchange for 1 calcium as

Increase cystolic calcium

Catecholamines

Positive inotropic = Contraction

Positive Lusitropic = Relaxation

Maintain adequate cardiac output when hr is increased

Positive inotropic effect

Increase in cystolic calcium via PKA-MED phosphorylation

Increase calcium influx via L-VACC

Increase Ca rel via RyR2

Increase Ca-sensitivity of tropomyosin complex

Positive lusitropic effect

increase rate of relaxation via accelerated reuptake of cystolic calcium into SR due to SECRA = increases phosphorylation of PLB