The influence of interferon(IFN)--y on vasodilation was examined in bovine isolated mesenteric arteries. Arterial nngs were incubated with lFN-y (100 U ml1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-’y markedly inhibited endothehum-dependent relaxation to bradykinin and impaired vasodilation to nitroprusside, which was endothelium-independent. The decrease in relaxation was correlated with a decrease in bradykinin-and nitroprusside-induced CGMP production. Relaxation to the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine or zapnnast was not altered after IFN--y, which suggests that the IFN--y effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after lFN-y, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with N#{176}-monomethyl-L-arginine during the 20-hr incubation with IFN-y completely prevented the decrease in relaxation and CGMP elevation to nitroprusside. We condude that IFN-’y induces a marked increase in release of arterial-derived nitric oxide resulting in a desensitization of guanylate cyclase, which contributes to a decrease in relaxation to bradykinin and nitroprusside. These results may implicate the existence of an important adaptive process in the regulation of vascular tone during pathological situations associated with the induction of nitric oxide synthesis.