Induction of nitric oxide release by interferon-gamma inhibits vasodilation and cyclic GMP increase in bovine isolated mesenteric arteries.
The influence of interferon (IFN)-gamma on vasodilation was examined in bovine isolated mesenteric arteries. Arterial rings were incubated with IFN-gamma (100 U ml-1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-gamma markedly inhibited endothelium-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 zaprinast was not altered after IFN-gamma, which suggests that the IFN-gamma effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after IFN-gamma, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine during the 20-hr incubation with IFN-gamma completely prevented the decrease in relaxation and cGMP elevation to nitroprusside. We conclude that IFN-gamma 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.
De Kimpe
S J
SJ
Department of Pharmacology, Faculty of Pharmacy, Utrecht University, The Netherlands.
Van Heuven-Nolsen
D
D
van Amsterdam
J G
JG
Radomski
M W
MW
Nijkamp
F P
FP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002417:Cattle; D006152:Cyclic GMP / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine