I-K independent class III actions of MS-551 compared with sematilide and dofetilide during reperfusion in anaesthetized rats

1 The antiarrhythmic and haemodynamic effects of three class III antiarrhythmic drugs, MS-551, sematilide and dofetilide, were examined in the coronary artery, ligation-reperfusion model of pentobarbitone-anaesthetized rats, a species deficient in functional cardiac I-K. MS-551 is a non-selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel (I-K) blockers. 2 Before coronary ligation, 3 and 10 mg kg(-1) MS-551 decreased the heart rate by 6% (P<0.01) and 12% (P<0.01), and increased mean arterial pressure (MAP) by 14% (P<0.05) and 33% (P<0.01), respectively. Sematilide at 10 and 30 mg kg(-1) also decreased the heart rate by 4% (P<0.01) and 9% (P<0.01), respectively, and the higher dose of 30 mg kg(-1) decreased MAP by 29% (P<0.01). Dofetilide, 1 mg kg(-1), decreased the heart rate (P<0.01), but had no significant effect on MAP. 3 The QT interval was increased by 10% (P<0.01) and 31% (P<0.01), when 3 and 10 mg kg(-1) MS-551 were given. Sematilide and dofetilide had no effect on the QT interval. 4 Immediately after reperfusion, lethal ventricular fibrillation (VF) was induced in 80% of the saline group. MS-551 at 3 and 10 mg kg(-1), reduced the incidence of lethal VF to 50% and 20% (P<0.05). Neither dofetilide 1 mg kg(-1) nor sematilide (10 and 30 mg kg(-1)) decreased the incidence of lethal VF (70%, 80% and 50%, respectively). None of the three drugs had any effect on the occurrence of reperfusion-induced VT or the total incidence of VF. However, LD mg kg(-1) MS-551 delayed the onset of reperfusion-induced VF (27+/-5 s compared with 12+/-2 s of the control group, P<0.05). 5 In conclusion, in rats which are deficient in cardiac IK MS-551 prolonged the QT interval and reduced the incidence of sustained VF after reperfusion. Blockade of channels other than IK might participate in the defibrillatory effect of MS-551. Sematilide and dofetilide, which are selective IK blockers, did not increase the QT interval nor did they show antiarrhythmic effects. Mechanisms other than K channel block may be involved in the different effects of the three drugs on blood pressure.