Effectiveness of antiarrhythmic agents in preventing death in ventricular fibrillation induced by isoprenaline in desoxycorticosterone-pretreated rats

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Abstract
The effectiveness of the β-adrenoceptor blocking agents 1-, d-, dl-propranolol, practolol and sotalol and the antiarrhythmic drugs quinidine, lignocaine, phenytoin and verapamil in preventing isoprenaline-induced death in ventricular fibrillation was assessed in unanaesthetised desoxycorticosterone (DOCA) pretreated rats. The animals were implanted subcutaneously (sc) with a wax pellet containing 20 mg of DOCA and drank 1% saline. After a period of 3 to 4 weeks of this treatment, rats were challenged with one single, sc, dose of 150 μg·kg−1 of isoprenaline. Death occurred 20.3± 10.4 min (mean±SD) after isoprenaline in 37 out of 38 rats. Antiarrhythmic agents, injected sc 20 min before isoprenaline injection, prevented death with the following ED50 (mg·kg−1): 1-propranolol, 0.16; dl-propranolol, 0.24; practolol, 1.93; sotalol, 6.50; d-propranolol, 6.80; quinidine, 49.4;lignocaine, 78.2;phenytoin, 397.6. Verapamil, at the dose of 35 mg·kg−1, prevented death in nine out of 22 rats (41%). Higher doses of verapamil diminished survival rates. Bulk myocardial content of Na+, K+, Mg2+ and Ca2+, expressed in meq·kg−1 wet weight (mean±SD), was determined immediately after death in ventricular fibrillation or after killing 60 to 70 min after isoprenaline challenge. Prior to the injection of isoprenaline, rats pretreated with DOCA-saline exhibited a lower myocardial content of K+ (69.0±3.4) and Mg2+ (16.1 ±1.0) than untreated controls (K+, 79.3 ±5.8; Mg2+, 19.5 ± 1.6). Isoprenaline did not alter the cardiac content of the four cations in untreated rats, but it further decreased the K+ levels to 63.4±2.8 and elevated Na+ from 41.3± 1.8 to 50.2±3.8 in DOCA-saline pretreated rats. No net changes in Ca2+ were observed. None of the antiarrhythmic agents altered myocardial Na+ increase, but β-adrenergic antagonists obviated myocardial Mg2+ and K+ loss induced by isoprenaline. These data demonstrate that the DOCA-saline model is useful for the screening of antiarrhythmic drugs and that changes in myocardial electrolytes may serve to distinguish agents possessing β-adrenoceptor blocking properties from other antiarrhythmic agents.

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