Cardiac Muscle: Excitation, Contraction, Relaxation and Regulation Flashcards
Determinants of Membrane Potential
o To a first approximation, the Vm at any given time is given by:
(conductane of NA/ total conductance) * E Na + (conductane of K/ total conductance) * E K
Cardiac Activation Sequence
SA Node AV node bundle of his bundle brances purjinke fibres Ventricle
Ventricular Action Potential
4 phases
0- rapid depolarisation from Na entry
1-initial repolarisation from K out, to balance charge
2=Plateau - slow entry of CA
3-Slow K+ repolarisation out
4=diastolic potential maintained by NA/K pump
Potassium
iK channel permeability,
which is very low in resting cells, increases
with depolarization. Channels carrying the iK current are activated near
the end of Phase 0, but opening of the channels carrying this current is
delayed until the end of phase 2
Chronotropic state
The ‘beat’ frequency of cardiac muscle twitches can be varied by:
Alteration of Vthreshold
Alteration of rate of spontaneous depolarization of the pacemaker
potential ( Sympathetic and Parasympathetic)
Sources of calcium to active contraction
Extracellular
• (i) Voltage dependent (L-type) calcium channels in the
sarcolemmal (including T-tubular) membranes
• (ii) Passive (voltage-independent) leakage channels in the
sarcolemma
§ Intracellular
• (i) SR (via CICR)
• (ii) Mitochondria
§ Calcium can be removed from the cytoplasm (thereby permitting
relaxation) in one of two ways:
• (i) Extrusion across the sarcolemmal membrane
• (ii) Sequestration into the SR (and mitochondria)
• In most species, the balance of these two processes favours net
uptake by the SR whenever twitch frequency increases
Mechanisms for removal of calcium:
SERCA, Na-Ca Exchange,Ca ATPase
§ Mitochondrial Uniporter
SERCA
1 Ca : 1 ATP pumps Ca back into SR
Na-Ca Exchange
NCX
sarcolemmal Na-Ca
exchanger whose stoichiometry is 3Na:1Ca.
driven by the steep
Na concentration gradient across the sarcolemma to extrude Ca
NCX can operate in both directions
depending on the membrane potential
In cardiac muscle, local calcium release events were discovered in isolated ventricular myocytes. o The microscopic release events were terms ‘\_\_\_\_\_\_ \_\_\_\_\_\_’
calcium sparks o Experimental data supports the idea that calcium release from the SR is quantized into these fundamental ‘calcium spark’ events. o During the AP, tens of thousands of these sparks are activated to form the cell wide transient.
Mitochondrial involvement
Mitochondria can take up a considerable amount of Ca via a channel across the
inner membrane
o [Ca2+]m modulates the activity of: pyruvate…thereby enhancing the rate of
oxidative phosphorylation
o Hence the myocardial metabolic rate reflects the average value of [Ca2+]m
which, in turn, reflects the average value of [Ca2+]myoplasm
Factors that affect myofilament calcium sensitivity:
Acidosis Sarcomere length Catecholamines ATP Caffeine Inorganic [PO4]i
Factors that affect myofilament calcium sensitivity:
Acidosis- decr Sarcomere length- incr Catecholamines ( adrenaline/ noradrenaline)- decr ATP- decr Caffeine- incr Inorganic [PO4]i- decr
Contraction force depends on _________________ in a highly non-linear way
o Contraction generates both isometric force (as ventricular pressure) and rapid
shortening or isotonic contraction (ejection phase).
intracellular and total calcium
o Two main ways to change the strength of contraction:
§ Altering the calcium transient (amplitude and duration)
§ Altering myofilament calcium sensitivity
Force-Frequency Relationship
o Each AP, calcium enters the cell
o Increasing HR leads to:
§ Less time for calcium extrusion
§ A decrease in the average membrane potential which decreases overall
calcium efflux via the NCX
§ Increased numbers of APs lead to increased intracellular Na and Ca via
effect on NCX
o Overall effect is to “load” the SR
Frank Starling Law
An increase in EDV increases stroke volume via a stretch-induced increase in
cardiac contractility
In failing hearts, the effect on ____with increasing frequency
that is seen in healthy hearts is not present
• Potentially _________ is not phosphorylated, therefore no
increase in the rate at which SERCA can take up calcium to SR
SERCA
phospholamban
Modulation by Neurotransmitters
o Heart it innervated by the ANS
Parasympathetic (cholinergic muscarinic effects, vagal) decreases SA node
discharge rate, reduces intracellular calcium concentration and hence force
o Sympathetic nerves
§ Increase SA node discharge rate
§ Increase calcium influx via calcium channels (ICa)
§ Increase SERCA rate (lusitropic effect)
§ Decrease sensitivity of troponin for Calcium (lusitropic effect)
(In order to assist relaxation)
𝛽-adrenergic effects.
Commence with the binding of a catecholamine to a 𝛽-receptor on the
sarcolemma which activates the membrane-bound stimulatory _____ _____
G protein,
𝛽-adrenergic G protein, directly effects
The Gs protein acts:
§ Directly to activate calcium channels (high threshold, probably DHPsensitive)
𝛽-adrenergic G protein, indirectly effects
Stimulate adenylyl cyclase which
↓
Catalyses production of cAMP from ATP which
↓
Activates protein kinase A /C (resident on the inner surface of the sarcolemma) whose catalytic subunit is
released and diffuses into the myoplasm causing Phosphorylation cascade of V-gated Ca channels, phospholambam,topononin I
𝛽-adrenergic effects Results in:
§ Increased contractility
§ Little change in maximum actin-activated myosin ATPase activity
§ But an approximate 2-fold increase of intracellular calcium required for
any given degree of activation of myosin ATPase activity (or force),
thus
§ The twitch (primarily the relaxation phase) is abbreviated without
decrement of force
𝛼-adrenergic Commence with the binding of a catecholamine to an 𝛼 receptor on the
sarcolemma which Activates the membrane bound stimulatory G protein, Gq, which
Activates phospholipase C which ↓ Catalyses the hydrolysis of PIP3 to IP3 and diacylglyercol. kinase C with phosphorylates: Calcium channels at residues different from those targeted by PKA, 𝛽-adrenergic receptors and G proteins IP3 enhances release of calcium from the SR resulting in: - A rise of intracellular calcium (and therefore increased CICR) - Increase of twitch force
Parasympathetic (cholinergic muscarinic) effects
Indirect G-protein induced enhancement of levels of cGMP
Direct coupling of atrial ACh receptors to a G-protein (GK)
result in
Reduction of the slope of the SAN pacemaker potential
§ Reduction of intracellular calcium
§ Modest diminution of contractility
Modulation of Force by Drugs
o Best known drugs are the cardiotonic steroids (e.g. digoxin, ouabain).
Increase [Na+]i by inhibiting the Na+ pump, hence reducing Calcium
extrusion by NCX
§ Sympathomimetics acting via 𝛽-1 receptors (limited by desensitisation)
§ Bipyridines act via phosphodiesterase (increase cAMP)
Modulation of Force by Drugs
Cardiac failure results in an increase in ventricular dimensions which decreases
efficiency (from Laplace)
§ Hence current therapies are targeted at reversing the increase in cardiac
dimensions by decreasing filling pressure
- Nitric oxide donors to relax vasculature
- Diuretics to decrease blood volume (hence filling pressure)
- ACE inhibitors to depress angiotensin axis
