Mechanisms that produce nitric oxide-mediated relaxation of cerebral arteries during atherosclerosis.
OBJECTIVE
The first goal of the present study was to examine the hypothesis that relaxation of cerebral arteries to nitric oxide in primates is dependent on activation of soluble guanylate cyclase (sGC). The second goal was to determine whether the role of sGC in mediating responses to nitric oxide is altered in atherosclerosis.


METHODS
Basilar arteries from normal and atherosclerotic monkeys were studied in vitro. After precontraction with prostaglandin F(2alpha) (0.1 to 1 micromol/L), concentration-response curves to authentic nitric oxide (1 nmol/L to 1 micromol/L), sodium nitroprusside (10 nmol/L to 10 micromol/L; a nitric oxide donor), and papaverine (10 nmol/L to 10 micromol/L; a non-nitric oxide, non-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 micromol/L; an inhibitor of sGC). The effect of ODQ on basal tone of basilar arteries from normal and atherosclerotic monkeys was also examined.


RESULTS
Nitric oxide, sodium nitroprusside, and papaverine produced relaxation that was similar (P:>0.05) in normal and atherosclerotic monkeys. ODQ produced marked inhibition (P:<0.05) of vasorelaxation in response to nitric oxide and nitroprusside but not papaverine. For example, relaxation of the basilar artery in response to nitric oxide (0.1 micromol/L) was inhibited by approximately 85% and 73% by ODQ (1 micromol/L) in normal and atherosclerotic monkeys, respectively. ODQ produced contraction of the basilar arteries, and the increase in tension to ODQ was greater in normal (2.7+/-0.3 g; mean+/-SE) than in atherosclerotic monkeys (1.4+/-0.4 g; P:<0.05). In contrast, contraction to prostaglandin F(2alpha) 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 part, on activation of sGC and (2) the influence of sGC (via reduced production and/or activity of basal nitric oxide) on cerebral vascular tone is reduced in atherosclerosis.
Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, IA 52242-1081, USA.
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Didion
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Faraci
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D015237:Dinoprost / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D002537:Intracranial Arteriosclerosis / Q000378:metabolism* / Q000503:physiopathology; D008252:Macaca fascicularis; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; D009569:Nitric Oxide; D002784:Cholesterol; D015237:Dinoprost; D010208:Papaverine; D006162:Guanylate Cyclase