IK independent class III actions of MS‐551 compared with sematilide and dofetilide during reperfusion in anaesthetized rats

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Abstract
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 IK. MS‐551 is a non‐selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel (IK) 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, 10 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.

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