Effects of a novel inhibitor of guanylyl cyclase on dilator responses of mouse cerebral arterioles.
OBJECTIVE
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.
Sobey
C G
CG
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Faraci
F M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; D009599:Nitroprusside; D013482:Superoxide Dismutase; D006162:Guanylate Cyclase; D000109:Acetylcholine