RESPONSE OF CEREBRAL BLOOD-VESSELS TO AN ENDOGENOUS INHIBITOR OF NITRIC-OXIDE SYNTHASE

We examined effects of N-G,N-G-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 mu M 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 mu m. ADMA (10 and 100 mu M) produced marked inhibition of vasodilation in response to acetylcholine without inhibiting vasodilatation in response to nitroprusside. ADMA (1-100 mu M) inhibited activity of brain NO synthase (measured as the conversion of L-[C-14]arginine to L-[C-14]citrulline). In cerebrum and cerebellum, 50% inhibition of activity of NO synthase was produced by 2.3 +/- 0.4 and 1.8 +/- 0.1 mu M ADMA, respectively. In rabbits, treatment with ADMA (300 mu M decreased baseline diameter of cerebral arterioles (control diameter = 93 +/- 10 mu m) by 11 +/- 2% (P < 0.05, n = 10). In response to 1 mu M 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.