Initiation Of The Heart Beat And Excitation Contraction Coupling - pediagenosis
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Thursday, March 23, 2023

Initiation Of The Heart Beat And Excitation Contraction Coupling

Initiation Of The Heart Beat And Excitation – Contraction  Coupling

Initiation Of The Heart Beat And Excitation–Contraction  Coupling

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.

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