The pharmacology of adenosine and angiotensin II (AII) suggests that endogenous adenosine could function to regulate some of the biological effects of AII. The goal of this study was to test the hypothesis that endogenous adenosine inhibits the ability of AII to potentiate noradrenergic neurotransmission and/or to directly contract vascular smooth muscle. Two approaches were used to assess the physiological import of adenosine-AII interactions on neurotransmission and vascular tone. First, the effects of exogenous adenosine and AII, separately and in combination, on vascular responses to periarterial nerve stimulation (PNS) and vascular tone were determined. Second, the effects of an adenosine receptor antagonist, 1,3-dipropyl-8-p-sulfophenylxanthine, on AII-induced potentiation of vascular responses to PNS and on AII-induced direct vasoconstriction were examined. All studies were conducted in the in situ blood perfused rat mesentery. Intra-arterial and i.v. infusions of AII potentiated responses to PNS and increased vascular tone, whereas i.a. infusions of adenosine had the opposite effects. Intra-arterial infusions of adenosine potentiated the ability of i.a. AII to enhance responses to PNS; however, i.a. adenosine attenuated the direct vasoconstrictive action of i.a. AII. Intra-arterial infusions of 1,3-dipropyl-8-p-sulfophenylxanthine, at a dose which antagonized the effects of exogenous adenosine, did not alter the effects of either i.a. AII or i.v. AII on vascular responses to PNS or on vascular tone. These results indicate that although adenosine has the potential to regulate AII-induced enhancement of noradrenergic neurotransmission and AII-induced direct vasoconstriction, such regulation does not occur under the conditions of this study.