Antiarrhythmic and electrophysiological effects of GYKI-16638, a novel N-(phenoxyalkyl)- N-phenylalkylamine, in rabbits

Abstract

The effect of N-[4-[2- N-methyl- N-[1-methyl-2-(2,6-dimethylphenoxy)ethylamino]-ethyl]-phenyl]-methanesulfonamide.hydrochloride (GYKI-16638; 0.03 and 0.1 mg/kg, i.v.), a novel antiarrhythmic compound, was assessed and compared to that of d-sotalol (1 and 3 mg/kg, i.v.) on arrhythmias induced by 10 min of coronary artery occlusion and 10 min of reperfusion in anaesthetized rabbits. Also, its cellular electrophysiological effects were studied in rabbit right ventricular papillary muscle preparations and in rabbit single isolated ventricular myocytes. In anaesthetized rabbits, intravenous administration of 0.03 and 0.1 mg/kg GYKI-16638 and 1 and 3 mg/kg d-sotalol significantly increased survival during reperfusion (GYKI-16638: 82% and 77%, d-sotalol: 75% and 83% vs. 18% in controls, P<0.05, respectively). GYKI-16638 (0.1 mg/kg) significantly increased the number of animals that did not develop arrhythmias during reperfusion (46% vs. 0% in controls, P<0.05). In isolated rabbit right ventricular papillary muscle, 2 μM GYKI-16638, at 1 Hz stimulation frequency, lengthened the action potential duration at 50% and 90% repolarization (APD 50–90) without influencing the resting membrane potential and action potential amplitude (APA). It decreased the maximal rate of depolarization ( V max) in a use-dependent manner. This effect was statistically significant only at stimulation cycle lengths shorter than 700 ms. The offset kinetics of this V max block were relatively rapid, the corresponding time constant for recovery of V max was 328.2±65.0 ms. In patch-clamp experiments, performed in rabbit ventricular myocytes, 2 μM GYKI-16638 markedly depressed the rapid component of the delayed rectifier outward and moderately decreased the inward rectifier K + current without significantly altering the slow component of the delayed rectifier and transient outward K + currents. These results suggest that in rabbits, GYKI-16638 has an in vivo antiarrhythmic effect, comparable to that of d-sotalol, which can be best explained by its combined Class I/B and Class III actions.