The influence of digoxin on the systemic toxic effects of bupivacaine was studied in a rodent animal model. The experiment was undertaken with consideration to clinical situations such as pregnancy that are associated with the secretion of an endogenous digoxin-like factor. Twenty Wistar male rats, under barbiturate anesthesia and controlled ventilation, received either 5 micrograms/kg intravenous digoxin (n = 10) or saline (n = 10), blinded to the observer. Digoxin serum concentration was 1.8 +/- 0.24 ng/ml in the study group. Thirty minutes after digoxin or saline was administered, bupivacaine was infused at a constant rate of 2mg/kg/minute. The threshold doses of bupivacaine toxic effects (first ventricular arrhythmia, 25% fall of baseline heart rate, 25% fall of baseline mean arterial blood pressure, first seizure activity, isoelectric electroencephalogram, and asystole) were significantly lower in the digoxin group, as were the lethal bupivacaine serum concentrations. Digoxin, in hyperoxic nonacidotic rats, increases the cardiac and central nervous system toxicity of bupivacaine. Based on the known electrophysiologic actions of these two drugs, a synergistic toxic interaction is demonstrated.