Excitation–contraction coupling in myocardium: implications of calcium release and Na+–Ca2+ exchange

Abstract

In this paper, we present evidence in support of the hypothesis that electrogenic Na+–Ca2+ exchange is responsible for three phenomena in rat cardiac muscle: (i) the slow repolarization phase of the action potential, (ii) the time course of the mechanical recovery process, and (iii) the development of triggered arrhythmias. It was shown that the duration of the slow phase of repolarization of the action potential varies in proportion to the Na+ concentration gradient and inversely with the Ca2+ concentration gradient over the cell membrane. This suggested that Na+–Ca2+ exchange can generate a current of sufficient magnitude to maintain the membrane depolarized at a level of −60 mV. The mechanical restitution process of rat cardiac trabeculae was shown to exhibit three phase. The first phase, α, probably reflects rapid transport of calcium in the sarcoplasmic reticulum from the uptake sites to the release sites. After the initial increase of force during α, force rises further during phase β and then declines during phase γ. During all phases, force increases with the extracellular calcium concentration. β is accelerated by preceding extrasystoles, while an increase of the heart rate causes force to increase at approximately the same rate but to a higher level during phase β. These observations are compatible with a model in which the sarcoplasmic reticulum sequesters calcium from the cytosol, while the membrane of the sarcoplasmic reticulum is assumed to exhibit also a small leak of calcium into the cytosol. Net influx of calcium into sarcoplasmic reticulum during phase β diminishes with time after the heart beat, while the cytosolic calcium concentration gradually decreases as a result of the concerted activities of the Na+–K+ pump and Na+–Ca2+ exchanger. Cytosolic calcium decreases in 1.5 min after the last contraction sufficiently to cause a net calcium loss from the sarcoplasmic reticulum during the ensuing phase γ. In damaged trabeculae we observed triggered arrhythmias that were always preceded by propagating spontaneous contractions. Propagation of spontaneous contractions was consistent with spontaneous calcium release in the region of damage of the trabeculae as a result of a calcium overload of the sarcoplasmic reticulum. Calcium release in the damaged area causes calcium-induced calcium release in adjacent sites as a result of diffusion of calcium. Propagation velocity of the spontaneous contraction was consistent with this model. The occurrence of arrythmias was consistent with the hypothesis that the release of calcium during this process leads to a depolarization as a result of electrogenic Na+–Ca2+ exchange. The triggered action potential adds to the calcium load of the cells and thereby causes another spontaneous calcium release to repeat the cycle.