Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat

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Abstract
1 The actions of intravenous verapamil against arrhythmias induced by occlusion of a coronary artery were investigated in conscious rats. 2 Verapamil (2–20 mg kg−1, i.v. given pre-occlusion) dose-dependently reduced arrhythmias in rats with either large or small occluded zones at an ED50 of 6 mg kg−1. This dose was effective when given immediately post-occlusion. 3 Severe arrhythmias, as opposed to PVC, were preferentially reduced. 4 In conscious, and pentobarbitone-anaesthetized rats, verapamil (6 mg kg−1) had different effects on electrically-induced arrhythmias, and the ECG, from an equi-effective anti-arrhythmic dose of quinidine (20 mg kg−1, i.v.). Quinidine decreased following frequency, but increased threshold current and pulse width, whereas verapamil did not. Both drugs increased P-R interval, but only quinidine increased QRS and Q-T intervals. 5 Thirty minutes post-occlusion, the verapamil content of tissue and blood was determined after a 6 mg kg−1 dose given pre- or post-occlusion. Measurable levels of verapamil were found in both normal and ischaemic myocardium. Plasma and plasma water concentrations were 3.6 ± 0.8 μmol l−1 and 0.6 ± 0.1 μmol l−1 (x̄ ± s.e.mean), respectively following post-occlusion administration vs. 2.7 ± 1.2 and 0.24 ± 0.04 for pre-occlusion administration. 6 Plasma water concentrations were close to IC50 values for inhibition of contractility in rat atria and ventricles. Similar concentrations depressed slow action potentials induced in rat ventricles by raised K+ 7 We suggest that the ability of verapamil to prevent severe ventricular arrhythmias following myocardial ischaemia in the conscious rat is largely due to the calcium antagonist effects of the drug.

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