Effects of E-4031, almokalant and tedisamil on postrest action potential duration of human papillary muscles

The new antiarrhythmic compounds E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl- aminobenzoyl)piperidine), almokalant and tedisamil prolonged the action potential duration (APD) of human right ventricular papillary muscle. In order to investigate whether drug-channel interaction takes place during rest, regular stimulation (0.5 Hz) was interrupted by three 30-min periods of quiescence. Drug was added at the beginning of the second period of rest, the third period was interposed at equilibrium of drug action. Under predrug control conditions, the first action potential after rest was longer than with regular stimulation, steady state was reached again with a monotonic time course. With E-4031 the first action potential after 30 min of drug exposure during quiescence was similar to predrug control, but drug-induced prolongation of APD developed during further stimulation, indicating drug interaction with open channels. After the third period of quiescence, the first APD remained significantly increased compared to predrug values suggesting that E-4031 may be trapped within the resting channel. With almokalant, however, the first APD after wash-in was already prolonged and APD increased further with regular pacing. The effect was partially reversed during the third period of rest. These findings are compatible with open-channel block or no evidence for trapping. On the other hand, tedisamil prolonged APD but did not change the monophasic time course neither when added during quiescence nor at equilibrium of drug action. It is concluded that changes in APD after quiescence indicate differences among these drugs in their interactions with channel subtypes controlling repolarization.