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 p otentials and measurements of ventricular paced QT intervals. Twenty m ale volunteers were studied during almokalant infusion aiming at plasm a 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 ve ntricular paced QT interval was measured during incremental stimulatio n from the apical region (RVAPEX) and the outflow tract (RVOT) of the right ventricle, and the frequency dependence was analyzed using a lin ear regression model. At an almokalant dose of Cpl greater than or equ al to 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 extrasystoles increased in parallel over th e range of coupling intervals studied and was significantly prolonged at Cpl 100 and 150. The ratio between the MAPD of the extrasystoles an d preceding beats was unaltered after almokalant infusion. The ventric ular paced QT intervals increased during almokalant infusion in a simi lar manner as that of the MAPD. During RVAPEX stimulation, the prolong ation was more pronounced at low heart rates, an effect that was not s een during RVOT stimulation. Almokalant significantly prolonged the MA PD at dose levels Cpl greater than or equal to 50. There was no eviden ce 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 RVAP EX stimulation.