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

The effect of N-[4-[2-N-methyl-N-[1-methyl-2-(2,6-dimethylphenoxy)ethylamin o]-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 ra bbits. Also, its cellular rlectrophysiological effects were studied in rabb it right ventricular papillary muscle preparations and in rabbit single iso lated ventricular myocytes. In anaesthetized rabbits, intravenous administr ation of 0.03 and 0.1 mg/kg GYKI-16638 and 1 and 3 mg/kg D-sotalol signific antly increased survival during reperfusion (GYKI-16638: 82% and 77%, D-sot alol: 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 deve lop arrhythmias during reperfusion (46% vs. 0% in controls, P < 0.05). In i solated rabbit right ventricular papillary muscle, 2 mu M GYKI-16638, at 1 Hz stimulation Frequency, lengthened the action potential duration at 50% a nd 90% repolarization (APD(50-90)) without influencing the resting membrane potential and action potential amplitude (APA). It decreased the maximal r ate of depolarization (V-max) in a use-dependent manner. This effect was st atistically significant only at stimulation cycle lengths shorter than 700 ms. The offset kinetics of this V-max block were relatively rapid, the corr esponding time constant for recovery of V-max was 328.2 +/- 65.0 ms. In pat ch-clamp experiments, performed in rabbit ventricular myocytes, 2 mu M GYKI -16638 markedly depressed the rapid component of the delayed rectifier outw ard and moderately decreased the inward rectifier K+ current without signif icantly 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 ca n be best explained by its combined Class I/B and Class III actions. (C) 20 00 Elsevier Science B.V. All rights reserved.