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-Adrenergic stimulation modulates Ca²⁺- and voltage-dependent inactivation of L-type Ca²⁺ channel currents in guinea-pig ventricular myocytes

Ian Findlay

The objective of this study was to examine the effect of -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 (_f ~15 ms) was reduced to the same extent by ryanodine (_f ~30 ms) and the absence of Ca²⁺ (_f ~30 ms) while the slow phase of inactivation (_s ~70 ms) was reduced by ryanodine (_s ~160 ms) and further reduced in the absence of Ca²⁺ (_s ~300 ms). In isoproterenol, biphasic inactivation of Ca²⁺ currents (_f ~4 ms, _s ~60 ms) was replaced by a single slow ( ~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.

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