Previous work in anesthetized rats has demonstrated that the sensitivity to cardiotoxic actions of cardiotonic steroids is increased in senescence, and studies in crude homogenates and partially purified membrane preparations have suggested that this altered responsiveness is related to an aging-associated reduction in the sarcolemmal content of Na,K-adenosine triphosphatase. This decrease in Na,K-adenosine triphosphatase could enhance the sensitivity to digitalis-like compounds by reducing the reserve capacity of the Na+-pump and thus the extent of digitalis-induced pump inhibition required before the onset of toxicity. Current experiments examined dose-dependent actions of digoxin in atrial muscle isolated from 3-, 12- and 24- to 25-month-old rats and determined if alterations in responsiveness correlated with changes in ouabain-sensitive 86Rb+ uptake rate, an estimate of Na+-pump activity. Atrial preparations from aged rats were more sensitive to the cardiotoxic actions of digoxin; however, the inotropic efficacy before the onset of toxicity was not affected by age. Both 1) the maximum attainable ouabain-sensitive 86Rb+ uptake rate and 2) the difference between maximum uptake rate and that monitored in preparations stimulated at 4.0 Hz decreased progressively with age. These results indicate that atrial muscle from aged rats is more sensitive to direct toxic effects of digoxin and suggest that this lower tolerance is mediated, at least in part, by a reduction in Na+-pump reserve capacity.