Frequency-dependent increase in cardiac Ca2+ current is due to reduced Ca2+ release by the sarcoplasmic reticulum

Ca2+-current facilitation describes several features of increase in current amplitude often associated with a reduction in inactivation rate. The aim of this study was to investigate the mechanism of frequency-dependent increase in L-type Ca2+ current, I-Ca taking advantage of recent knowledge on the control of Ca2+ current inactivation in cardiac cells. The frequency-dependent increase in I-Ca was studied in adult rat ventricular myocytes using the whole-cell patch-clamp technique. I-Ca was elicited by a train of 200-ms depolarizing pulses to +20mV applied at various frequencies (0.2 up to 1.3 Hz). The increase in frequency induced a rate-dependent enhancement of I-Ca or facilitation phenomena. In most cells, that showed two inactivation phases of I-Ca facilitation was mainly related to slowing of the fast I-Ca inactivation phase that occurred besides increase in peak I-Ca amplitude. Both the decrease and slowing of the fast component of inactivation phase were attenuated on beta-adrenergic-stimulated current. Frequency-dependent I-Ca facilitation paralleled a reduction in Ca2+ transient measured with fluo-3. After blocking sarcoplasmic reticulum-Ca2+ release by thapsigargin, the fast I-Ca inactivation phase was reduced and facilitation was eliminated, Facilitation could not then be restored by 1 mu M isoprenaline. Thus in rat ventricular myocytes, frequency-dependent facilitation of I-Ca reflects a reduced Ca2+-dependent inactivation consecutive, in most part, to reduced Ca2+ load and Ca2+ release by the sarcoplasmic reticulum rather than being an intrinsic characteristic of the L-type Ca2+ channel.