The aim of this study was to evaluate the pro-arrhythmic effects of class III anti-arrhythmic drugs. We studied pure IKr (rapid component of delayed rectifier potassium current) blockers (dofetilide and D-sotalol) versus pure IKs (slow component of delayed rectifier potassium current) blockers (chromanol 293B and HMR 1556) in the same preparation. Moreover, we have compared these results with a recent class III agent, azimilide which blocks the two IKdr (delayed rectifier potassium current) components. We studied the effects of these drugs on the action potential (AP) parameters recorded using the microelectrode technique. The occurrence of early afterdepolarisations (EADs) in the presence or not of adrenaline was also analysed.
Rabbits were humanely killed according to the ethical standards of the French Ministry of Research. Purkinje fibres were dissected and superfused with Tyrode solution. Each drug at different concentrations (from 10-9 to 10-5 M, n = 9 for each agent at each concentration) were added alone during 30 min and then with adrenaline (10-8 M) during the following 30 min. Shift of pacing cycle length from 1000 to 2000 ms was done to evaluate the influence of bradycardia on EAD elicitation. Modulations of AP duration are expressed as means ± S.E.M. Statistical analysis of AP parameters was performed using ANOVA followed by a Dunnet’s test (intragroup comparison) and an ANOVA for multiple factors (intergroup comparison). Non-parametric factors were compared using an exact Fischer test. P < 0.05 was considered as statistically significant.
Pure IKr blockers and azimilide significantly increased AP duration measured at 90 % of repolarisation (APD90) in a dose-dependent manner. At concentrations inducing similar prolongation of APD90 (respectively by 46.3 ± 4.9, 35.4 ± 3.7 and 43 ± 3.7 % for the following drugs), dofetilide (5 X 10-9 M), D-sotalol (10-5 M) and azimilide (5 X 10-7 M) promoted EADs respectively in three, six and one cases of nine experiments under adrenergic stimulation. Pure IKs blockers failed to increase APD90 in our conditions and did not induce EADs. Besides, results demonstrated that EAD occurrence is potentiated by bradycardia and adrenergic stimulation.
We concluded that class III anti-arrhythmic drugs that block IKr showed more pro-arrhythmic effects than those that block IKs. Azimilide seemed to be the most promising class III compound as it exhibited low pro-arrhythmic effects, despite its ability to lengthen cardiac AP duration, contrary to chromanol 293B and HMR 1556, which failed to increase APD90.