Assessment of frequency dependency of the class III effects of almokalant: a study using programmed stimulation and recording of monophasic action potentials and ventricular paced QT intervals.

The aim of the present study was to assess the frequency dependency of the effects of almokalant, a selective class III antiarrhythmic drug, on ventricular repolarization using recordings of monophasic action potentials and measurements of ventricular paced QT intervals. Twenty male volunteers were studied during almokalant infusion aiming at plasma concentrations (Cpl) of 20, 50, 100, and 150 nmol/l. The duration of monophasic action potential at 90% repolarization (MAPD) was measured during incremental and premature ventricular extrastimulation. The ventricular paced QT interval was measured during incremental stimulation from the apical region (RV APEX) and the outflow tract (RVOT) of the right ventricle, and the frequency dependence was analyzed using a linear regression model. At an almokalant dose of Cpl > or = 50, there was a significant prolongation of the MAPD of 10-15%. The prolongation was of equal magnitude at all paced cycle lengths (CL). The MAPD of ventricular extrasystole increased in parallel over the range of coupling intervals studied and was significantly prolonged at Cpl 100 and 150. The ratio between the MAPD of the extrasystoles and preceding beats was unaltered after almokalant infusion. The ventricular paced QT intervals increased during almokalant infusion in a similar manner as that of the MAPD. During RV APEX stimulation, the prolongation was more pronounced at low heart rates, an effect that was not seen during RV OT stimulation. Almokalant significantly prolonged the MAPD at dose levels Cpl > or = 50. There was no evidence of a frequency dependence of this effect. The ventricular paced QT intervals were prolonged in a similar manner as that of the MAPD, and this effect exhibited a small reverse frequency dependence during RV APEX stimulation.