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

"Ca(2+)-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 +20 mV 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 microM isoprenaline. Thus in rat ventricular myocytes, frequency-dependent facilitation of I(Ca)reflects a reduced Ca(2+)-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.