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Effects of dantrolene sodium in rodent models of cardiac arrhythmia
R R Brooks1, J F Carpenter, S M Jones
1Norwich Eaton Pharmaceuticals, Inc., New York 13815.
Abstract:
Dantrolene sodium has been compared with reference antiarrhythmic agents in rodent models of cardiac arrhythmia. In a coronary-artery-ligation model in rats, dantrolene sodium (3, 10 and 20 mg/kg i.v.) significantly decreased extrasystoles, episodes of ventricular tachyarrhythmia, and frequency, duration, and total episodes of ventricular fibrillation in a dose-dependent manner. In an electrically induced fibrillation model in rats, dantrolene sodium (10 and 20 mg/kg i.v.) significantly raised ventricular fibrillation threshold in a dose- and time-dependent manner. In contrast to its activity in these models, dantrolene sodium was not active in two chemically induced models involving automaticity. Aconitine-induced arrhythmias in rats and mice and ouabain-induced arrhythmias in guinea pigs were not suppressed by i.v. (10 or 20 mg/kg) or i.p. (100-3000 mg/kg) doses of the drug. These results show that the antiarrhythmic potential of dantrolene sodium, predicted by in vitro Class III and Class IV electrophysiological effects, is expressed in whole animal models.
Insights
Dantrolene sodium effectively reduced cardiac arrhythmias in rodent models, demonstrating dose-dependent antiarrhythmic properties. However, it did not suppress chemically induced arrhythmias related to automaticity.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Electrophysiology
Background:
- Cardiac arrhythmias pose a significant clinical challenge.
- Dantrolene sodium exhibits in vitro electrophysiological effects suggesting antiarrhythmic potential.
- Rodent models are crucial for evaluating antiarrhythmic drug efficacy.
Purpose of the Study:
- To evaluate the antiarrhythmic efficacy of dantrolene sodium in rodent models.
- To compare its effects with reference antiarrhythmic agents.
- To investigate its activity in different types of induced cardiac arrhythmias.
Main Methods:
- Dantrolene sodium was administered intravenously (i.v.) and intraperitoneally (i.p.) in various rodent models.
- Models included coronary-artery ligation and electrical stimulation for inducing fibrillation.
- Chemically induced models (aconitine, ouabain) were used to assess effects on automaticity.
Main Results:
- Dantrolene sodium significantly decreased ventricular arrhythmias in a dose-dependent manner in ligation and electrical models.
- It dose- and time-dependently increased the ventricular fibrillation threshold.
- The drug showed no efficacy in suppressing aconitine- or ouabain-induced arrhythmias.
Conclusions:
- Dantrolene sodium demonstrates significant antiarrhythmic potential in rodent models of cardiac ischemia and electrical instability.
- Its efficacy is linked to its in vitro Class III and Class IV electrophysiological actions.
- Dantrolene sodium's antiarrhythmic effects are model-dependent, particularly regarding automaticity.