PATHOPHYSIOLOGIC EFFECTS OF SPONTANEOUS CA2+ RELEASE IN THE HEART

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We tested the hypothesis that the occurrence of spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in the cardiac diastole might be a mechanism for the? saturation of systolic contractile function upon exposure to inotropic perturbations that increase cell Ca loading. ln rat myocytes we observed (1) in the steady state that regardless of drugs or the stimulation frequency, the bathing Cao at which the twitch amplitude saturated varied linearly with the occurrence of spontaneous Ca2+ release and (2) in the transient state following previous stimulation the extent of rest potentiation of the twitch amplitude in rat myocytes was also limited by the occurrence of spontaneous Ca release. A mathematical model that incorporates this interaction between potential-mediated SR Ca2+ release and the occurrence of spontaneous Ca release in individual cells was constructed to predict the behavior of intact multicellular muscle. The microscopic, myofilament motion caused by spontaneous SR Ca2+ release in muscles produces scattered light intensity fluctuations (SLIF) in a laser beam scattered by the tissue. Using novel time- gated SLIF we studied the relationship of SLIF and tension during time-gated intervals following electrical stimulation. In a given muscle the maximum twitch amplitude occurs at approximately the same level of SLIF: when this level is exceeded, either transiently during monotonic or oscillatory recovery following stimulation in a given Cao, or in the steady rested state by an increase in Cao, twitch tension decreases. This behavior in intact muscle was predicted by model derived from data in individual cells. Thus, the occurrence of spontaneous SR Ca release is a plausible mechanism for the saturation of the inotropic response to Ca2+ in the intact myocardium.