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.
Levesque
P C
PC
Department of Physiology, University of Nevada School of Medicine, Reno 89557-0046.
Clark
C D
CD
Zakarov
S I
SI
Rosenshtraukh
L V
LV
Hume
J R
JR
D000200:Action Potentials; D000818:Animals; D000838:Anions; D000873:Anthracenes / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002412:Cations; D018118:Chloride Channels; D000242:Cyclic AMP / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D016276:Ventricular Function
D000838:Anions; D000873:Anthracenes; D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D002412:Cations; D018118:Chloride Channels; D008565:Membrane Proteins; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; C063968:E 4031; C010030:9-anthroic acid; D000242:Cyclic AMP; D007545:Isoproterenol