In healthy humans, ganglionic blockade unmasks a clear age-related decrease in cardiac responses to isoproterenol but not to epinephrine. We postulated that an age-related decrease in neuronal uptake (which affects epinephrine, but not isoproterenol) may offset a parallel decrease in -receptor mediated responses. To test this concept, nine young (mean 29±2 yrs of age) and 8 older (mean 61±2 yrs of age) healthy subjects were infused on 3 different study-mornings with epinephrine at increasing rates, either alone or combined with desipramine to eliminate differences in neuronal uptake or with desipramine and trimetaphan to induce ganglionic blockade and thereby also eliminate differences in arterial baroreflex activity. Epinephrine caused the expected rate-related increases in systolic BP, heart rate, stroke volume, ejection fraction and cardiac index. Except for the systolic BP, the extent of the changes was similar in young and older subjects. After desipramine, cardiac responsiveness to epinephrine was markedly enhanced, but more (p<0.01) in young versus older subjects for heart rate and cardiac index (+14 vs 7 bpm and +1.6 vs 1.1 L/min/m² at 20 ng/kg/min). Combined with desipramine and trimetaphan, cardiac responses to epinephrine were further enhanced, again more (p<0.01) in young subjects, resulting in large differences in the increases in heart rate as well as ejection fraction (+29 vs 17 bpm and +14 vs 7% at 20 ng/kg/min). The present study shows that "healthy aging" in humans is associated with decreased cardiac responsiveness to the -agonist epinephrine, but it appears that this decrease can be balanced by concomitant decreases in buffering of these responses by neuronal uptake and the arterial baroreflex.