The objective of this study was to examine the effects of isoproterenol (isoprenaline) and carbachol upon voltage-dependent inactivation of L-type Ca2+ current (ICa,L). ICa,L was recorded in guinea-pig isolated ventricular myocytes in the presence and absence of extracellular Ca2+ to separate total inactivation and voltage-dependent inactivation. In the presence of Ca2+, isoproterenol and carbachol had ‘competitive’ effects upon the relationships between membrane voltage and ICa,L amplitude and inactivation. Neither agonist had a marked effect upon the decay of inward ICa,L carried by Ca2+. In the absence of Ca2+, isoproterenol severely reduced and slowed ICa,L inactivation; this effect was reversed by carbachol. Under control conditions decay was dominated by fast inactivation. Isoproterenol reduced fast-inactivating and increased time-independent currents in a dose-dependent manner. These effects were counteracted by carbachol. There was a reciprocal relationship between the amplitude of fast-inactivating and time-independent currents with agonist stimulation. It is concluded that agonist modulation of rapid voltage-dependent inactivation of L-type Ca2+ channels involves an ‘on-off’ switch
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