In contrast to the sympathetic nervous system, which is activated by aging in at least some sympathetic nervous outflows, epinephrine release from the adrenal medulla appears to be either normal or low in the elderly. Using isotope dilution methodology, we studied the effect of aging on the secretion of epinephrine in 19 men, aged 20-30 yr, and 15 men, aged 60-75 yr. Measurements were made both at rest and during the application of laboratory stressors, as diminished adrenal medullary responsiveness possibly contributes to the impairment of some cardiovascular and metabolic responses to stress described previously in the elderly. Epinephrine secretion at rest was lower in the older men (mean +/- SEM, 0.86 +/- 0.10 nmol/min) than in the younger men (1.45 +/- 0.17 nmol/min; P < 0.05). Due to 20% lower plasma epinephrine clearance in the older men (P < 0.01), the reduction in the plasma concentration of epinephrine (0.37 +/- 0.03 vs. 0.52 +/- 0.06 nmol/L; P = 0.06) was proportionally less than that in epinephrine secretion. In the younger men, epinephrine secretion doubled or tripled during mental stress, isometric exercise, and dynamic exercise. Epinephrine responses to the stressors were reduced in older men, being equivalent to only 44% (P < 0.05), 44% (P = 0.1), and 33% (P = 0.01) of the corresponding responses in the younger men. After uptake from plasma, in some circumstances epinephrine is released from sympathetic nerves as a cotransmitter, where it can augment the release of the major sympathetic transmitter, norepinephrine. We also measured regional extraadrenal release of epinephrine from the heart to test whether the previously described increased release of norepinephrine from the cardiac sympathetic nerves with aging might result from facilitator effects of epinephrine released as a cotransmitter. At rest, epinephrine was released from the heart (9.4 +/- 2.6 pmol/min) in older men only (P < 0.01) despite the fact that adrenal medullary secretion of epinephrine was reduced. Failure of epinephrine and norepinephrine spillover from the heart to increase in parallel in the elderly during the sympathetic excitation accompanying exercise suggested that epinephrine lay outside the sympathetic nerves, perhaps arising from extraneuronal synthesis in the heart. We have not yet tested whether extraneuronal, in contrast to neuronal, epinephrine release in the heart could contribute to the observed higher rates of norepinephrine release in the elderly.