The process linking depolarization to contraction is called excitation - contraction coupling. The basics of action potentials (APs) are
described in Chapter 5.
Cardiac muscle electrophysiology
Ventricular muscle action
potential (Fig. 19a). The
resting potential of ventricular myocytes is approximately −90 mV (close to EK)
and stable (phase 4; Fig. 19a). An AP is initiated when the myocyte is
depolarized to a threshold potential of approximately −65 mV, as a
result of transmission from an adjacent myocyte via gap junctions (Chapter
17). Fast, voltage-gated Na+ channels are activated, leading to an inward current which depolarizes the
membrane rapidly towards +30 mV.
This initial depolarization or upstroke (phase 0; Fig. 19a) is similar
to that in nerve and skeletal muscle, and assists transmission to the next
myocyte. The Na+ current rapidly inactivates, but, in cardiac
myocytes, the initial depolarization activates voltage-gated Ca2+ channels
(L-type channels; threshold approximately −45 mV), through which Ca2+
floods into the cell. The resultant inward current prevents the cell from
repolarizing, and causes a plateau phase (phase 2; Fig. 19a) that is
maintained for ∼250 ms until the L-type channels inactivate. The cardiac AP is thus much
longer than that in nerve or skeletal muscle (∼300 ms vs ∼2 ms).
Repolarization occurs due to activation of a voltage-gated outward K+ current
(phase 3; Fig. 19a). The plateau and associated Ca2+ entry are
essential for contraction; the blockade of L-type channels (e.g. dihydropyridines)
reduces force. As the AP lasts almost as long as contraction (Fig. 19b), its refractory
period (Chapter 5) prevents another AP being initiated until the muscle
relaxes; thus, cardiac muscle cannot exhibit tetanus (Chapter 14).
The sinoatrial node and origin
of the heart beat
The sinoatrial node (SA node) AP
differs from that in ventricular muscle (Fig. 19c). The resting potential
starts at a more positive value (approximately −60 mV) and decays steadily with
time until it reaches a threshold of around −40 mV, when an AP is initiated.
The upstroke of the AP is slow, as it is not due to the activation of
fast Na+ channels, but instead slow L-type Ca2+ channels;
the SA node contains no functional fast Na+ channels. The slow upstroke means
that conduction between SA nodal myocytes is slow; this is particularly
important in the atrioventricular node (AV node), which has a
similar AP. The rate of decay of the SA node resting potential determines the
time it takes to reach threshold and to generate another AP, and hence deter-
mines the heart rate; it is therefore called the pacemaker potential.
The pacemaker potential decays because of a slowly reducing outward K+
current set against inward currents. Factors that affect these currents alter
the rate of decay and the time to reach threshold, and hence the heart rate,
and are called chronotropic agents. The sympathetic transmitter,
noradrenaline (norepinephrine), is a positive chronotrope that increases
the rate of decay and thus the heart rate, whereas the parasympathetic
transmitter, acetylcholine, lengthens the time to reach threshold and
decreases the heart rate (Fig. 19d).
Action potentials elsewhere in
the heart (Fig. 19e). Atria
have a similar but more triangular AP compared to the ventricles. Purkinje
fibres in the conduction system are also similar to
ventricular myocytes, but have a spike (phase 1) at the peak of the upstroke,
reflecting a larger Na+ current that contributes to their fast conduction
velocity (Chapter 6). Other atrial cells, the AV node, bundle of His and Purkinje
system may also exhibit decaying resting potentials that can act as pacemakers.
However, the SA node is normally fastest and predominates. This is called dominance
or overdrive suppression.
Excitation–contraction coupling
(Fig. 19f) Contraction. Cardiac muscle contracts
when intracellular Ca2+ rises above 100 nm. Although Ca2+
entry during the AP is essential for contraction, it only accounts for ∼25% of
the rise in intracellular Ca2+. The rest is released from Ca2+
stores in the sarcoplasmic reticulum (SR). APs
travel down invaginations of
the sarcolemma called T-tubules, which are close to,
but do not touch, the terminal cisternae of the SR. During the AP
plateau, Ca2+ enters the cell
and activates Ca2+-sensitive Ca2+ release
channels in the SR, allowing stored Ca2+ to flood into the
cytosol; this is Ca2+-induced Ca2+ release (CICR). The amount of Ca2+
released depends on how much is stored and how much Ca2+ enters
during the AP. Modulation of the latter is a key way in which cardiac muscle
force is regulated (see below). Peak intracellular [Ca2+] normally
rises to ∼2 μm, although maximum contraction occurs above 10 μm.
Relaxation. Ca2+ is rapidly pumped back into
the SR (sequestered) by adenosine triphosphate (ATP)-dependent Ca2+
pumps (Ca2+ ATPase)
. However, Ca2+ that
entered the myocyte during the AP must also be removed again. This is primarily
performed by the Na+–Ca2+ exchanger
in the membrane, which pumps one Ca2+ ion out in exchange for
three Na+ ions, using the Na+ electrochemical gradient as
an energy source. This is relatively slow, and continues during diastole. If
the latter is shortened, i.e. when the heart rate rises, more Ca2+
is left inside the cell and the cardiac force increases. This is the staircase
or Treppe effect.
Regulation of contractility:
inotropic agents (Fig. 19f)
Sympathetic stimulation increases
cardiac muscle contractility (Chapter 20) because it causes the release
of noradrenaline, a positive inotrope. Noradrenaline binds to
β1-adrenoceptors on the membrane and causes increased Ca2+ entry via
L-type Ca2+ channels during the AP , and thus increases Ca2+
release from the SR ( ; see above). Noradrenaline also accelerates Ca2+
sequestration into the SR. The contractility is also increased by slowing the
removal of Ca2+ from the myocyte. Cardiac glycosides (e.g. digoxin)
inhibit the Na+ pump which removes Na+ from the cell (Chapter 4). Intracellular
[Na+] therefore increases and the Na+ gradient across the membrane
is reduced. This depresses Na+–Ca2+ exchange, which
relies on the Na+ gradient for its motive force, and Ca2+ is
pumped out of the
cell less rapidly. Consequently, more Ca2+ is available inside the
myocyte for the next beat, and
force increases. Acidosis (blood pH < 7.3) is negatively
inotropic, largely because H+ competes for Ca2+-binding sites.
