Cellular electrophysiologic responses of isolated neonatal and adult cardiac fibers to d-sotalol

AbstractThe short-term cellular electrophysiologic actions of d-sotalol on isolated neonatal and adult canine ventricular myocardium and Purkinje fibers were evaluated using standard microelectrode techniques. d-Sotalol, 10−6to 10−4M, had no effects on action potential amplitude, maximal diastolic potential or action potential upstroke velocity (Vmax) in any neonatal or adult preparation. In five adult myocardial preparations, d-sotalol produced concentration-dependent increases in action potential duration at 50% (APD50) and 90% (APD90) repolarization and effective refractory period. In six neonatal myocardial preparations, d-sotalol produced a biphasic response; APD50, APD90and effective refractory period decreased at 10−6and 10−5M. At 10−4M, these values increased significantly but to a lesser extent compared with values in adults.In seven adult Purkinje fibers, d-Sotalol significantly increased APD50, APD90and effective refractory period in a concentration-dependent manner. All six neonatal Purkinje fibers responded in a biphasic manner, with values for APD50, APD90and effective refractory period being less than control at 10−6Mand near control values at 10−5M. At 10−4M, these variables were significantly increased, but to a lesser extent than in audlt preparations. Our data confirm the typical class III effects of d-sotalol in adult cardiac tissues. The shortening of repolarization and refractoriness at lower drug concentrations in developing cardiac tissues may relate to age-dependent differences in cellular ionic function and basic electrophysiology

Electrophysiologic effects of a new anitarrhythmic agent, recainam, on isolated canine and rabbit myocardial fibers

AbstractRecainam (Wy 42,362) is a new antiarrhythmic agent undergoing clinical evaluation, but its electrophysiologic effects in cardiac muscle are poorly defined. With microelectrode techniques, its profile in isolated preparations of dog and rabbit hearts was determined using drug concentrations of 10 to 300 μM. Recainam induced a concentration and frequency-dependent decrease in the maximal rate of rise of ihe phase 0 of the action potential (Vmax), action potential amplitude and overshoot potential, with little or no change in the effective refractory period except in Purkinje fibers, in which it was markedly reduced. At a 300 μMconcentration, Vmaxwas reduced 51% (p < 0.001) in ventricular muscle and 44% (p < 0.001) in atrial muscle, with no change in action potential duration or effective refractory period. At the same drug concentration in Purkinje fibers, Vmaxwas decreased by 41% (p < 0.01), action potential duration at 90% repolarization by 36% (p < 0.01) and effective refractory period by 34% (p < 0.01). Recainam had no significant effect on the sinoatrial node, but it depressed phase 4 depolarization in isoproterenol-induced automaticity in Purkinje fibers. The drug had no effect on slow channel potentials induced by high concentrations of potassium and isoproterenol.The data indicate that the electrophysiologic profile of recainam in isolated cardiac muscle is consistent with the overall effects of class IC agents without having an effect on the slow calcium channel. Its major action is to depress Vmax, with little effect on refractoriness. As in the case of other class IC compounds, the differential effects of recainam on the action potential duration in ventricular muscle and Purkinje fibers may predispose to the drug's proarrhythmic actions by accentuating heterogeneity in refractoriness in the heart

Electrophysiological effects of MS-551, a new class III agent: comparison with dl-sotalol in dogs. J Pharmacol Exp Ther 285:687–694

ABSTRACT MS-551 is a newly synthesized, nonspecific K ϩ channel blocker. To elucidate its electrophysiological and potential proarrhythmic effects relative to those of dl-sotalol in vivo, serial changes in ECGs, endocardial and epicardial monophasic action potential durations, and left and right ventricular pressures were measured simultaneously in pentobarbital-anesthetized open-chest dogs. Complete heart block was produced by the injection of 37% formaldehyde into the atrioventricular node. Intravenous administration of MS-551 produced prolongation of action potential duration at 90% repolarization time (APD 90 ) immediately after the beginning of infusion and reached plateau at 10 min. MS-551 (1 mg/kg) caused 73 Ϯ 8% increase in APD 90 and 28 Ϯ 5% increase in QT c at basic cycle length of 700 msec. The maximal prolongation of APD 90 induced by 1 mg/kg MS-551 was 39% greater than that by the same dose of sotalol (P Ͻ .01). The dose-response curve of prolongation of ventricular effective refractory period produced by MS-551 was shifted significantly to the left compared with that induced by sotalol. The EC 50 was 0.5 Ϯ 0.1 mg/kg and 1.2 Ϯ 0.2 mg/kg for MS-551 and sotalol, respectively (P Ͻ .05). When 0.5 mg/kg MS-551 doses were used, no ventricular arrhythmia was induced by stimulation at 200-msec basic cycle length. When 1.5 mg/kg sotalol was administered, 5 of 15 developed torsade de pointes, 2 of 15 developed ventricular fibrillation and 5 of 15 developed sustained ventricular tachycardia. The idioventricular rates and left ventricular pressures were reduced significantly by sotalol, not by MS-551. In conclusion, MS-551 is a potent class III antiarrhythmic agent that selectively prolongs repolarization in the ventricular myocardium and appears to be devoid of autonomic effects. Dose for dose, it is more potent in prolonging the APD 90 and the right ventricular effective refractory period possibly with a lower tendency for the development of proarrhythmia in a canine heart-block model