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 (1H-[ 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 NG-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