Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase.
We examined effects of NG,NG-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, on cerebral vascular responses using cranial windows in anesthetized rats and rabbits. Under control conditions in rats, topical application of 10 and 100 microM ADMA constricted the basilar artery by 9 +/- 2 and 19 +/- 1% (SE; P < 0.05, n = 8), respectively, from a baseline diameter of 213 +/- 19 microns. ADMA (10 and 100 microM) produced marked inhibition of vasodilation in response to acetylcholine without inhibiting vasodilatation in response to nitroprusside. ADMA (1-100 microM) inhibited activity of brain NO synthase (measured as the conversion of L-[14C]arginine to L-[14C]citrulline). In cerebrum and cerebellum, 50% inhibition of activity of NO synthase was produced by 2.3 +/- 0.4 and 1.8 +/- 0.1 microM ADMA, respectively. In rabbits, treatment with ADMA (300 microM) decreased baseline diameter of cerebral arterioles (control diameter = 93 +/- 10 microns) by 11 +/- 2% (P < 0.05, n = 10). In response to 1 microM acetylcholine, cerebral arterioles dilated by 36 +/- 6 and 13 +/- 4% (P < 0.05 vs. control) in the absence and presence of ADMA, respectively. Effects of ADMA were prevented by L-arginine. Thus ADMA inhibits activity of brain NO synthase and relaxation of cerebral blood vessels in response to acetylcholine. Because ADMA is produced in relatively high concentrations in brain, it may be an important endogenous modulator of cerebral vascular tone under resting conditions and in response to vasoactive stimuli.
Faraci
F M
FM
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Brian
J E
JE
Heistad
D D
DD
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002956:Citrulline / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D002956:Citrulline; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase