Effects of a Novel Inhibitor of Guanylyl Cyclase on Dilator Responses of Mouse Cerebral Arterioles

Abstract

Background and Purpose Nitric oxide–induced vasodilatation is mediated by both cGMP-dependent and -independent mechanisms. Previous studies that examined the role of soluble guanylyl cyclase in cerebral vessels have used methylene blue and LY-83583, compounds that generate superoxide anion and are not specific for inhibition of soluble guanylyl cyclase. We examined the effects of ODQ (1 H -[1,2,4]oxadiazolo[4,3,- a ]quinoxalin-1-one), a novel and highly selective inhibitor of soluble guanylyl cyclase, on responses of cerebral arterioles. Methods The effects of ODQ on responses of cerebral arterioles to acetylcholine, nitroprusside, 8-bromo-cGMP, and adenosine were examined in anesthetized mice by means of a cranial window. The effects of two concentrations of ODQ were examined in the absence and presence of superoxide dismutase. The effects of N ^G -nitro- l -arginine, an inhibitor of nitric oxide synthase, were also tested. Results ODQ (3 and 10 μmol/L) produced concentration-dependent inhibition of dilatation of cerebral arterioles (control diameter=29±1 μm) (mean±SE) in response to acetylcholine and nitroprusside. For example, 10 μmol/L acetylcholine and 1 μmol/L nitroprusside dilated cerebral arterioles by 28±3% and 44±2% in the absence and 6±2% and 7±1%, respectively, in the presence of 10 μmol/L ODQ ( P <.05 versus control). The inhibitory effects of ODQ were not altered by superoxide dismutase. Vasodilatation in response to 8-bromo-cGMP and adenosine was not inhibited by ODQ. N ^G -Nitro- l -arginine (100 μmol/L), an inhibitor of nitric oxide synthase, inhibited responses to acetylcholine by approximately 80% but tended to enhance responses to nitroprusside. Conclusions Thus, nitric oxide–mediated dilatation of mouse cerebral arterioles is profoundly inhibited by ODQ, an inhibitor of activity of soluble guanylyl cyclase. Cerebral vasodilator responses to adenosine and 8-bromo-cGMP were preserved in the presence of ODQ, indicating that inhibition by ODQ was selective. In contrast to previously used inhibitors of soluble guanylyl cyclase (methylene blue and LY-83583), the effects of ODQ are not mediated by generation of superoxide anion.