Electromechanical Action of Dofetilide and D-Sotalol During Simulated Metabolic Acidosis in Isolated Guinea Pig Ventricular Muscle

We examined the electromechanical effects of two class III antiarrhythmic agents, dofetilide (UK-68,798) and D-sotalol, in acidic myocardium. Right ventricular papillary muscle preparations isolated from guinea pigs were divided into three groups (n = 6 per group)(a) drug-free, (b) dofetilide (10 nM), and (c) D-sotalol (30 μM). At normal extracellular pH (pH = 7.32 ± 0.01), dofetilide and D-sotalol lengthened action potential duration (APD) to a similar extent, i.e., by 18–20%. Effective refractory period (ERP) increased in parallel, whereas membrane diastolic potential (MDP), action potential amplitude (APA), maximum velocity of depolarization ( max), and developed force (DF) were not significantly affected. Metabolic acidosis (pH = 6.78 ± 0.01) was simulated by reducing the bicarbonate concentration of the Tyrodeʼs solution from 20 to 6 mM. Superfusion with acidic solution alone for 30 min markedly decreased max and DF, whereas APD and ERP were lengthened slightly. The acidosis-induced decreases in max and DF were not affected by pretreatment with dofetilide or D-sotalol. In acidic superfusate, both agents still significantly increased APD and ERP to the same extent that they did at normal pH. The results indicate that metabolic acidosis, a major component of myocardial ischemia, does not attenuate the class III antiarrhythmic action of dofetilide and D-sotalol.