Beta-adrenergic and Muscarinic Agonists Modulate Inactivation of L-type Ca2+ Channel Currents in Guinea-pig Ventricular Myocytes

The objective of this study was to examine the effects of isoproterenol (isoprenaline) and carbachol upon voltage-dependent inactivation of L-type Ca(2+) current (I(Ca,L)). I(Ca,L) was recorded in guinea-pig isolated ventricular myocytes in the presence and absence of extracellular Ca(2+) to separate total inactivation and voltage-dependent inactivation. In the presence of Ca(2+), isoproterenol and carbachol had 'competitive' effects upon the relationships between membrane voltage and I(Ca,L) amplitude and inactivation. Neither agonist had a marked effect upon the decay of inward I(Ca,L) carried by Ca(2+). In the absence of Ca(2+), isoproterenol severely reduced and slowed I(Ca,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 Ca(2+) channels involves an 'on-off' switch.