The effect of age on presynaptic alpha2 adrenoceptor-mediated regulation of norepinephrine (NE) release was studied in hearts isolated from male fischer 344 rats 6-, 12-and 24-months of age. Cocaine (10−6M) and metanephrine (10−5M) were added to the perfusion fluid separately and in combination to block neuronal and extraneuronal uptake mechanisms, respectively. The amount of ne overflow in the effluent was significantly lower with increasing age at any given frequency of nerve stimulation. Metanephrine increased NE overflow in heart preparations of 12-and 24-month-old animals only. Yohimbine, a selective alpha2 adrenoceptor antagonist, at concentrations of 10−6M and 3 × 10−6M significantly increased the amount of NE overflow only in the perfusion effluent of hearts isolated from 6-month-old animals. These results suggest that extraneuronal uptake mechanisms increase with age and that presynaptic alpha2 adrenoceptor-mediated autoregulation of NE decreases with age. The findings could account, at least in part, for the decrease in adrenergic control of the heart shown to occur with age.