ANION AND CATION MODULATION OF THE GUINEA-PIG VENTRICULAR ACTION-POTENTIAL DURING BETA-ADRENOCEPTOR STIMULATION

Modulation of the ventricular action potential by beta-adrenergic activation of Ca2+, K+ and cyclic adenosine monophosphate (cAMP)-dependent Cl- channels was assessed in enzymatically isolated guinea-pig ventricular myocytes. The effectiveness and relative selectivity of 9-anthracene carboxylic acid (9-AC), as an antagonist of cAMP-dependent Cl- channels was also tested. Membrane currents and action potentials were recorded using the conventional whole-cell variant of the patch-clamp technique or with the amphotericin B perforated-patch technique. The beta-adrenergic agonist isoproterenol either increased or decreased action potential duration depending on whether the dominant effect was on inward Ca2+ currents or on outward K+ or Cl- currents. When Ca2+ and K+ channel modulation was prevented by nisoldipine and low temperature respectively, beta-adrenergic activation of Cl- channels caused a significant reduction in action potential duration and a slight depolarization of the membrane potential. The beta-adrenergic-mediated effects were reversed by the Cl- channel blocker, 9-AC. In the absence of beta-adrenergic stimulation, 9-AC had no detectable effects on action potentials or Ca2+ currents. These results suggest that beta-adrenergic activation of Cl- channels is a potent mechanism for regulation of action potential duration and that 9-AC may be a useful, relatively specific, pharmacological tool for evaluating the physiological role of cAMP-activated Cl- channels in heart. 9-AC also reversed the ability of isoproterenol to antagonize prolongation of action potential duration by the class III antiarrhythmic agent E-4031.