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 mumol/L) produced concentration-dependent inhibition of dilatation of cerebral arterioles (control diameter = 29 +/- 1 microns) (mean +/- SE) in response to acetylcholine and nitroprusside. For example, 10 mumol/L acetylcholine and 1 mumol/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 mumol/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. NG-Nitro-L-arginine (100 mumol/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.