STIMULATION OF CA-INDUCED CA RELEASE ONLY TRANSIENTLY INCREASES THE SYSTOLIC CA TRANSIENT - MEASUREMENTS OF CA FLUXES AND SARCOPLASMIC-RETICULUM CA

Objective: To investigate the effects of stimulating calcium induced C a release with low concentrations (100-200 mu M) Of caffeine and, in p articular, to stud; the cellular mechanisms responsible for the transi ent responses found previously. Methods: Experiments were performed on isolated rat ventricular myocytes. Intracellular calcium concentratio n ([Ca2+](i)) was measured with Indo-1, the cells were voltage-clamped with the perforated patch technique and sarcoplasmic reticulum (s.r.) Ca content was estimated from the integral of the caffeine-evoked cur rent. Results: The systolic Ca transient produced by the first depolar ization in the presence of caffeine was larger than the control. Over the next few pulses the magnitude of the Ca transient returned to cont rol levels despite the maintained presence of caffeine. The s.r. Ca co ntent was decreased by 9% after one pulse in caffeine and by 21% after several pulses in caffeine. The first pulse in the low concentration of caffeine was followed by an enhanced inward (Na-Ca exchange) curren t tail indicating increased efflux of calcium from the cell. The extra loss of calcium calculated from the tail current agreed quantitativel y with that from the change of s.r. Ca content. Conclusions: These res ults show that stimulating calcium induced calcium release produces on ly a transient increase of the systolic Ca transient. This is due to t he larger Ca transient decreasing the s.r. Ca content. It is concluded that any agent whose sole mode of action is stimulation of calcium-in duced calcium release will not produce a maintained inotropic effect. The consequences of this for the effects of other modulators of calciu m induced calcium release are discussed. (C) 1998 Elsevier Science B.V .