Mechanisms that produce nitric oxide-mediated relaxation of cerebral arteries during atherosclerosis

Background and Purpose-The first goal of the present study was to examine t he hypothesis that relaxation of cerebral arteries to nitric oxide in prima tes is dependent on activation of soluble guanylate cyclase (sGC). The seco nd goal was to determine whether the rule of sGC in mediating responses to nitric oxide is altered in atherosclerosis. Methods-Basilar arteries from normal and atherosclerotic monkeys were studi ed in vitro. After precontraction with prostaglandin F-2 alpha (0.1 to 1 mu mol/L), concentration-response curves to authentic nitric oxide (1 nmol/L to 1 mu mol/L), sodium nitroprusside (10 nmol/L to 10 mu mol/L; a nitric ox ide donor), and papaverine (10 nmol/L to 10 mu mol/L; a non-nitric oxide, n on-sGC-dependent stimulus) were generated in the presence and absence of 1H -[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 and 10 mu mol/L; an inhi bitor of sGC). The effect of ODQ on basal tone of basilar arteries from nor mal and atherosclerotic monkeys was also examined. Results-Nitric oxide, sodium nitroprusside, and papaverine produced relaxat ion that was similar (P>0.05) in normal and atherosclerotic monkeys. ODQ pr oduced marked inhibition (P<0.05) of vasorelaxation in response to nitric o xide and nitroprusside but not papaverine, For example, relaxation of the b asilar artery in response to nitric oxide (0.1 <mu>mol/L) was inhibited by approximately 85% and 73% by ODQ(1 mu mol/L) in normal and atherosclerotic monkeys, respectively. ODQ produced contraction of the basilar arteries, an d the increase in tension to ODQ was greater in normal (2.7+/-03 g; mean+/- SE) than in atherosclerotic monkeys (1.4+/-0.4 g; P<0.05). In contrast, con traction to prostaglandin F-2<alpha> was similar in the basilar artery from normal and atherosclerotic monkeys. Conclusions-These findings suggest that (1) relaxation of cerebral arteries in primates in response to nitric oxide is normally dependent, in large pa rt, on activation of sGC and (2) the influence of sGC (via reduced producti on and/or activity of basal nitric oxide) on cerebral vascular tone is redu ced in atherosclerosis.