beta-Adrenergic stimulation modulates Ca2+- and voltage-dependent inactivation of L-type Ca2+ channel currents in...

The objective of this study was to examine the effect of beta-adrenergic stimulation upon voltage- and Ca2+-induced inactivation of native cardiac L-type Ca2+ channels. Whole-cell currents were recorded from guinea-pig isolated ventricular myocytes. Total and voltage-dependent inactivation was separated by replacing extracellular Ca2+ with Mg2+. L-type Ca2+ channel behaviour was monitored with outward Ca2+ channel currents. First, the voltage dependence of inactivation was studied at fixed times (50 and 1000 ms) after activation. This showed that under control conditions Ca2+ contributed little to inactivation. In isoproterenol (isoprenaline), voltage-dependent inactivation was markedly reduced and Ca2+ contributed largely to total inactivation. Second, the time dependence of inactivation was studied at a fixed voltage (+10 mV). In control conditions the fast phase of inactivation (tau(f) approximately 15 ms) was reduced to the same extent by ryanodine (tau(f) approximately 30 ms) and the absence of Ca2+ (tau(f) approximately 30 ms) while the slow phase of inactivation (tau(s) approximately 70 ms) was reduced by ryanodine (tau(s) approximately 160 ms) and further reduced in the absence of Ca2+ (tau(s) approximately 300 ms). In isoproterenol, biphasic inactivation of Ca2+ currents (tau(f) approximately 4 ms, tau(s) approximately 60 ms) was replaced by a single slow (tau approximately 450 ms) phase of inactivation in the absence of Ca2+. It is concluded that, under control conditions Ca2+ channel current decay is largely dominated by rapid voltage-dependent inactivation, while in isoproterenol this is replaced by Ca2+-induced inactivation.