Cardiac Muscle: Excitation, Contraction, Relaxation and Regulation

Question 1

Determinants of Membrane Potential

o To a first approximation, the Vm at any given time is given by:

Answer 1

(conductane of NA/ total conductance) * E Na + (conductane of K/ total conductance) * E K

Question 2

Cardiac Activation Sequence

Answer 2

SA Node 
AV node bundle of his 
bundle brances 
purjinke fibres
Ventricle

Question 3

Ventricular Action Potential

4 phases

Answer 3

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

Question 4

Potassium

iK channel permeability,

Answer 4

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

Question 5

Chronotropic state

The ‘beat’ frequency of cardiac muscle twitches can be varied by:

Answer 5

Alteration of Vthreshold
Alteration of rate of spontaneous depolarization of the pacemaker
potential ( Sympathetic and Parasympathetic)

Question 6

Sources of calcium to active contraction

Answer 6

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

Question 7

§ Calcium can be removed from the cytoplasm (thereby permitting
relaxation) in one of two ways:

Answer 7

• (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

Question 8

Mechanisms for removal of calcium:

Answer 8

SERCA, Na-Ca Exchange,Ca ATPase

§ Mitochondrial Uniporter

Question 9

SERCA

Answer 9

1 Ca : 1 ATP pumps Ca back into SR

Question 10

Na-Ca Exchange

NCX

Answer 10

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

Question 11

In cardiac muscle, local calcium
release events were discovered in
isolated ventricular myocytes.
o The microscopic release events
were terms ‘\_\_\_\_\_\_ \_\_\_\_\_\_’

Answer 11

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.

Question 12

Mitochondrial involvement

Answer 12

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

Question 13

Factors that affect myofilament calcium sensitivity:

Answer 13

Acidosis
Sarcomere length
Catecholamines
ATP
Caffeine
Inorganic [PO4]i

Question 14

Factors that affect myofilament calcium sensitivity:

Answer 14

Acidosis- decr
Sarcomere length- incr
Catecholamines ( adrenaline/ noradrenaline)- decr
ATP- decr
Caffeine- incr
Inorganic [PO4]i- decr

Question 15

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).

Answer 15

intracellular and total calcium

Question 16

o Two main ways to change the strength of contraction:

Answer 16

§ Altering the calcium transient (amplitude and duration)

§ Altering myofilament calcium sensitivity

Question 17

Force-Frequency Relationship
o Each AP, calcium enters the cell
o Increasing HR leads to:

Answer 17

§ 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

Question 18

Frank Starling Law

Answer 18

An increase in EDV increases stroke volume via a stretch-induced increase in
cardiac contractility

Question 19

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

Answer 19

SERCA

phospholamban

Question 20

Modulation by Neurotransmitters

o Heart it innervated by the ANS

Answer 20

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)

Question 21

𝛽-adrenergic effects.
Commence with the binding of a catecholamine to a 𝛽-receptor on the
sarcolemma which activates the membrane-bound stimulatory _____ _____

Answer 21

G protein,

Question 22

𝛽-adrenergic G protein, directly effects

Answer 22

The Gs protein acts:

§ Directly to activate calcium channels (high threshold, probably DHPsensitive)

Question 23

𝛽-adrenergic G protein, indirectly effects

Answer 23

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

Question 24

𝛽-adrenergic effects Results in:

Answer 24

§ 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

Question 25

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

Answer 25

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

Question 26

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

Answer 26

Reduction of the slope of the SAN pacemaker potential
§ Reduction of intracellular calcium
§ Modest diminution of contractility

Question 27

Modulation of Force by Drugs

o Best known drugs are the cardiotonic steroids (e.g. digoxin, ouabain).

Answer 27

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)

Question 28

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

Answer 28

• Nitric oxide donors to relax vasculature
• Diuretics to decrease blood volume (hence filling pressure)
• ACE inhibitors to depress angiotensin axis