It is generally accepted that the sensitivity to toxic effects of digitalis increases with advancing age; however, the relative contribution of pharmacokinetics and pharmacodynamics to this aging-related change is presently unknown. The current study was designed to determine if senescence affects digitalis tolerance in an animal model and if observed changes are mediated by altered cardiac or autonomic nervous system responsiveness. Male, F344 rats of three age groups (4, 14 and 25 months) were anesthetized and infused intravenously with digoxin at a rate of 880 micrograms/kg per min. Two separate anesthetic regimens were employed: (a) an age-adjusted dose of urethane in spontaneously breathing animals (AR1); and (b) a non-age-adjusted dose of alpha-chloralose plus urethane in mechanically ventilated rats (AR2). Heart rate, EKG and arterial blood pressure were monitored continuously; baroreceptor reflex function was estimated before and 10 min following the start of digoxin infusion by examining the response to bilateral carotid occlusion. The infusion time required for digoxin-induced AV-dissociation was significantly reduced by senescence in rats anesthetized by AR1. However, doses of digoxin required to elicit ventricular extrasystoles and death were not significantly different among age groups in this anesthetized model and serum digoxin levels did not differ at the time of cardiac arrest. Similarly, AR2 animals showed a significant aging-related decrease in the time to AV-dissociation. However, in contrast to AR1, animals in AR2 displayed an aging-associated increase in the doses of digoxin required to produce ventricular arrhythmias and cardiac arrest. Thus, results suggest that aging in the F344 rat may, by pharmacodynamic mechanisms, promote the sensitivity to digoxin-induced AV-dissociation but not to ventricular arrhythmias or cardiac arrest.