FREQUENCY-DEPENDENT EFFECTS OF E-4031, ALMOKALANT, DOFETILIDE AND TEDISAMIL ON ACTION-POTENTIAL DURATION - NO EVIDENCE FOR REVERSE USE-DEPENDENT BLOCK

Antiarrhythmic drugs with class III action are incriminated by ''reverse use dependency'' which implies preferential block of resting channels (Hondeghem and Snyders 1990). The purpose of the present study was to investigate the frequency dependence of the effects of four new antiarrhythmic compounds on action potential duration (APD) in guinea-pig papillary muscle and on delayed rectifier in guinea-pig ventricular myocytes in order to scrutinize the concept of reverse use dependency and to obtain evidence for drug-channel interaction. In guinea-pig papillary muscles, E-4031 (1-[2-(6-methyl-2-pridyl)ethyl]-4-(4-methylsulfonyl-aminobenzoyl)piperidine), almokalant, dofetilide and tedisamil prolonged APD in a concentration-dependent manner. Drug-induced APD prolongation was not affected significantly by low rates of stimulation (0.2 to 0.5 Hz. In order to investigate whether drug-channel interaction takes places during rest, regular stimulation (1 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 steady state of drug action. With E-4031 and dofetilide no change in shape of the first AP after the initial 30 min of drug exposure was observed as compared with pre-drug control, but regular stimulation was required for the full effect to develop. APD did not recover to pre-drug values after the third period of quiescence. With almokalant and tedisa0mil, however, the first APD after wash-in was already prolonged and the effects increased further with regular pacing. Only with almokalant but not with tedisamil did APD recover during rest. In voltage-clamped guinea-pig myocytes, the rapidly activating component of the delayed rectifier was blocked in an analogous manner. From these findings it is concluded that the four drugs investigated do not bind preferentially to closed channels, instead, open channel block develops with repetitive activation. Therefore, the frequency-dependence of APD prolongation by class III antiarrhythmics must be explained by another mechanism than ''reverse use dependency'' of block.