Do calcium antagonists (verapamil, prenylamine, flunarizine, cinnarizine) reduce ischaemia-induced arrhythmias in a rat model of coronary artery occlusion?
Calcium antagonists suppress ischaemia-induced arrhythmias in a rat model, but this protective effect is limited to a narrow concentration range, with higher doses increasing mortality.
In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.
Fagbemi et al. (1984) studied this question.