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Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo
Author(s) -
Rees D.D.,
Palmer R.M.J.,
Schulz R.,
Hodson H.F.,
Moncada S.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14151.x
Subject(s) - omega n methylarginine , nitric oxide synthase , endothelium , nitroarginine , chemistry , nitric oxide , acetylcholine , endocrinology , blood vessel , arginine , bradykinin , medicine , endothelium derived relaxing factor , pharmacology , biology , biochemistry , amino acid , receptor
1 Three analogues of l ‐arginine were characterized as inhibitors of endothelial nitric oxide (NO) synthase by measuring their effect on the endothelial NO synthase from porcine aortae, on the vascular tone of rings of rat aorta and on the blood pressure of the anaesthetized rat. 2 N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA), N‐iminoethyl‐ l ‐ornithine ( l ‐NIO) and N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME; all at 0.1–100 μ m ) caused concentration‐dependent inhibition of the Ca 2+ ‐dependent endothelial NO synthase from porcine aortae. 3 l ‐NMMA, l ‐NIO and l ‐NAME caused an endothelium‐dependent contraction and an inhibition of the endothelium‐dependent relaxation induced by acetylcholine (ACh) in aortic rings. 4 l ‐NMMA, l ‐NIO and l ‐NAME (0.03–300 mg kg −1 , i.v.) induced a dose‐dependent increase in mean systemic arterial blood pressure accompanied by bradycardia. 5 l ‐NMMA, l ‐NIO and l ‐NAME (100 mg kg −1 , i.v.) inhibited significantly the hypotensive responses to ACh and bradykinin. 6 The increase in blood pressure and bradycardia produced by these compounds were reversed by l ‐arginine (30–100 mg kg −1 i.v.) in a dose‐dependent manner. 7 All of these effects were enantiomer specific. 8 These results indicate that l ‐NMMA, l ‐NIO and l ‐NAME are inhibitors of NO synthase in the vascular endothelium and confirm the important role of NO synthesis in the maintenance of vascular tone and blood pressure.