The effect of ATP and its congeners on the adrenergic neuroeffector transmission was evaluated in isolated blood vessels of the rabbit. ATP, ADP, AMP and adenosine inhibited the contractile response of the portal vein to adrenergic nerve stimulation, with a threshold concentration of the order of 0.1 muM and ED50 of about 1 microM. These agents, but not papaverine, inhibited the nerve stimulation-induced response in preference to the norepinephrine- or serotonin-induced response in the portal and saphenous veins and pulmonary and ear arteries. In the portal vein labeled with [3H]norepinephrine, ATP diminished the nerve stimulation-induced efflux of tritiated material. This nucleotide also reduced the KCl-induced tritium efflux but not the tyramine induced-efflux in the [3H]norepinephrine-labeled thoracic aorta. ATP had no significant effect on the uptake of [3H]norepinephrine in the portal vein, ear artery and thoracic aorta. Indomethacin and theophylline partially blocked the inhibitory action of ATP on the neurogenic constrictor response in some of the ear artery and saphenous vein preparations. Desipramine, atropine, propanolol, haloperidol and 2,2'-pyridylisatogen, a blocking agent against ATP in the taenia coli, were without such antagonistic effect. The results are consistent with a proposed negative feedback modulator role of ATP or a related purine compound in adrenergic transmission.