Acute and chronic effects of ketanserin on the electrophysiologic properties of isolated rabbit ventricular myocardium: particular reference to repolarization.

The acute and chronic cellular electrophysiologic actions of ketanserin, a selective blocker of 5-hydroxytriptamine (5-HT2) receptor, were examined in the isolated rabbit ventricular muscle. This work was prompted by the recent observations that small numbers of patients treated with hypertension develop QTc prolongation, rarely associated with torsades de pointes. At 1.0 Hz stimulation, ketanserin, 10(-5) and 10(-4) M, prolonged the action potential duration (APD) (by 20% and 29%, respectively) and voltage-dependent refractoriness. At 10(-4) M, the maximal rate of rise of phase 0 of the action potential (Vmax) decreased 11%. Action potential amplitude and resting membrane potential were not affected by either concentration of ketanserin used (10(-6) to 10(-4) M). Trains of stimuli at rates of 1.0 Hz or higher led to an exponential decline in Vmax to a new plateau level. The time constant for the recovery of Vmax from the use-dependent block was 1.3 second. Chronic administration of ketanserin (40 mg/kg/day, intramuscularly) caused a significant prolongation of APD (106%; p less than 0.01) and voltage-dependent refractoriness without effects on the action potential amplitude, resting membrane potential, and Vmax. These data indicate that ketanserin exerts significant class I effects with mild class III effects when superfused acutely, whereas chronic administration of ketanserin exhibits marked class III effects. Both effects of the drug are likely to exert significant antiarrhythmic actions.