Is cyclic AMP involved in the defibrillating effect of sotalol?
Ventricular fibrillation induced in animals pretreated with sotalol, a class III antiarrhythmic agent, would spontaneously terminate and revert into a sinus rhythm. This phenomenon has been attributed to the class III action of this drug, i.e., prolongation of myocardial action potential duration and effective refractory period. Since various observations suggested that these alone cannot explain the defibrillating phenomenon, we hypothesised that sotalol affected ventricular intercellular synchronization by increasing intercellular coupling. Our recent experimental studies have shown that sotalol antagonized the cellular decoupling to guinea pig ventricular muscle strip caused by perfusion with either a hypoxic normal Tyrode's solution or an oxygenated high Ca2+ Tyrode's solution. We assumed that the most likely mechanism for the restoration of intercellular coupling would be increasing intracellular cAMP concentration. In order to test this hypothesis, we studied the modification of this sotalol-induced recoupling by a cAMP dependent protein kinase inhibitor. The results clearly supported our assumption since the addition of Arg-Gly-Tyr-Ala-Leu- Gly (pure A- kinase inhibitor) prevented the aforementioned cellular recoupling action of sotalol in a dose-dependent manner. It can thus be concluded that changes in intracellular cAMP level are involved in the synchronizing / defibrillating effect of sotalol.
Miyachi
E
E
Department of Physiology, Fujita Health University, Toyoake, Japan.
Manoach
M
M
Uchiyama
H
H
Watanabe
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000378:metabolism; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects; D007546:Isoquinolines / Q000378:metabolism; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D013015:Sotalol / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; D005456:Fluorescent Dyes; D007546:Isoquinolines; D009842:Oligopeptides; C017475:lucifer yellow; D013015:Sotalol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases