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 curre nt amplitude often associated with a reduction in inactivation rate. The ai m of this study was to investigate the mechanism of frequency-dependent inc rease in L-type Ca2+ current, I-Ca taking advantage of recent knowledge on the control of Ca2+ current inactivation in cardiac cells. The frequency-de pendent increase in I-Ca was studied in adult rat ventricular myocytes usin g 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 w ere attenuated on beta-adrenergic-stimulated current. Frequency-dependent I -Ca facilitation paralleled a reduction in Ca2+ transient measured with flu o-3. After blocking sarcoplasmic reticulum-Ca2+ release by thapsigargin, th e fast I-Ca inactivation phase was reduced and facilitation was eliminated, Facilitation could not then be restored by 1 mu M isoprenaline. Thus in ra t 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.