Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations

Abstract

Objective: The aim was to study factors contributing to torsade de pointes in the acquired long QT syndrome. Methods: Anaesthetised rabbits or cats were given a continuous infusion of methoxamine and the class III agent almokalant (at a rate of 5 or 25 nmol·kg⁻¹·min⁻¹, respectively) and the effects on incidence of torsade de pointes and QT dispersion were examined. Effects of almokalant on action potentials recorded from Purkinje fibres and ventricular cells of rabbits and cats were also studied. Results: “High rate” infusion of almokalant prolonged the QT, interval [from 162(SEM 6.2) ms to 211(5.3) ms, p−1. During “low rate” infusion, 1/8 rabbits developed torsade de pointes (p = 0.0029) despite infusion of 900 nmol·kg⁻¹ almokalant and QT_C prolongation from 162(3.6) ms to 230(12.6) ms (pC dispersion increased from 15(1.7) ms to 32(5.6) ms (pC dispersion was unaltered. In six cats, high rate infusion induced a QT interval lengthening from 241(6.0) ms to 349(8.0) ms (pConclusions: The rate of infusion of repolarisation delaying agents may influence the dispersion of repolarisation and play a decisive role in the initiation of torsade de pointes. Cardiovascular Research 1993;27:2186-2193