β‐adrenergic and muscarinic agonists modulate inactivation of l‐type ca 2+ 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.