Central alpha receptors and their role in digoxin cardiotoxicity

The purpose of this study was to determine the role of alpha receptors in the inotropic and cardiotoxic actions of digoxin. Pentobarbital-anesthetized dogs were pretreated centrally with either prazosin, a selective alpha-1 antagonist, or yohimbine, a selective alpha-2 antagonist. Cardiac rhythm, blood pressure and contractile force were monitored during a 60-min period after pretreatment and during a continuous i.v. infusion of digoxin (2.5 micrograms/kg/min). Both agents, when administered into the lateral ventricle, produced depressant effects on hemodynamic parameters. Yohimbine (100 and 200 micrograms/kg i.c.v.) significantly increased the arrhythmogenic and lethal doses of digoxin in a dose-dependent manner. The protective effects of yohimbine (200 micrograms/kg) were not evident when the drug was given peripherally. Central alpha-1 blockade with prazosin increased the lethal dose of digoxin only at the largest dose (100 micrograms/kg i.c.v.) and its effects may be attributed to nonspecific central activity. BHT-933 (5 micrograms/kg i.c.v.), a selective alpha-2 agonist, enhanced the toxic effects of digoxin by decreasing both the arrhythmogenic and lethal dose of digoxin. These results suggest a central alpha-2 receptor mediation of the cardiotoxic actions of digoxin.