Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat

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 ED 50 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 IC 50 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.