Spontaneous calcium release from the sarcoplasmic reticulum in myocardial cells: mechanisms and consequences

Abstract

Under certain conditions of Ca2+ loading, cardiac myocytes, both isolated and in intact tissue, exhibit spontaneous, oscillatory Ca2+ transients due to Ca2+ release from the sarcoplasmic reticulum. These transients are not triggered by depolarization of the sarcolemma, though they themselves can generate depolarizing currents which can reach threshold to trigger an action potential. Spontaneous Ca2+ release occurs locally in a subcellular region and, once initiated, can propagate through the cell with a velocity of roughly 100 microns/s. Locally, the cytosolic Ca2+ concentration during spontaneous release is probably comparable to that during an electrically excited twitch. The mechanisms of initiation and propagation of spontaneous Ca2+ release are uncertain, but are probably closely related to the Ca2+-induced Ca2+ release which plays a role in normal excitation-contraction coupling. Spontaneous and triggered Ca2+ release appear to compete for a common pool of releasable sarcoplasmic reticulum Ca2+, with the result that spontaneous Ca2+ release imposes a beat-rate-dependent limit on the inotropic effect of interventions which increase intracellular Ca2+. Mathematical modeling of this effect shows that it can also explain increased diastolic tone, the development of aftercontractions and oscillatory restitution of contractility in states of 'Ca2+ overload'. Spontaneous Ca2+ release is a cause of arrhythmias, and may well play a role in some cases of systolic and diastolic myocardial dysfunction.