MS-551 AND KCB-328, 2 CLASS-III DRUGS AGGRAVATED ADRENALINE-INDUCED ARRHYTHMIAS

1 We investigated the proarrhythmic effects of MS-551 and KCB-328, cla ss III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 mu g/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrena line injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhyt hmic ratio (as calculated by dividing the number of ventricular premat ure contraction by the number of the total heart rate) and the severit y of arrhythmia were observed. 2 MS-551 infusion, 1 mg/kg/30 min, decr eased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interv al by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased th e latent interval of the adrenaline arrhythmias produced by the induci ng dose (30 +/- 2 s compared with 43 +/- 3 s of the control interval, P<0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmi as by non-inducing adrenaline doses (P<0.05). 3 Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared with MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and pro longed the QTc interval by 25% (P<0.01). During the 30 min of infusion , arrhythmias occurred in five out of seven dogs (TdP in two dogs). KC B-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31 +/- 3 s compared with 49 +/- 7 s o f the control period, P<0.05), but did not significantly alter the arr hythmic ratio. 4 Adrenaline induced TdP only after MS-551 or KCB-328 w as administered, i.e, after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. 5 T o examine the direct arrhythmogenic effect of MS-551 and whether an ad renergic mechanism plays some role on this arrhythmogenesis, a bolus i njection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arr hythmias in five out of seven dogs (TdP in one dog). Also in the propr anolol pre-treated dogs, MS-551 induced arrhythmias in five out of sev en dogs (TdP in 1 dog). 6 In conclusion, these observations indicate t hat MS-551 and KCB-328 induced arrhythmias and intensified proarrhythm ic effects of adrenaline, MS-551 being stronger than KCB-328 at the sa me QTc prolonging doses. The direct arrhythmogenic effect of MS-551 wa s not influenced by beta-blocker treatment.