l‐NG‐nitro arginine (l‐NOARG), a novel, l‐arginine‐reversible inhibitor of endothelium‐dependent vasodilatation in vitro

Abstract

The effect of l‐N G‐nitro arginine (l‐NOARG) was compared with that of l‐N G‐monomethyl arginine (l‐NMMA) on vasodilatation of the isolated aorta of the rabbit and perfused mesentery of the rat in response to acetylcholine (ACh) and sodium nitroprusside (NP). l‐NOARG (1.5–100 μ m) and l‐NMMA (3–100 μ m) produced concentration‐related contraction of the rabbit aorta precontracted with phenylephrine (700–900 n m). Similarly, l‐NOARG (10–200 μ m) and l‐NMMA (30–100 μ m) elevated perfusion pressure of the noradrenaline (NA, 0.6–2.5 m m)‐preconstricted rat mesentery preparation. l‐NOARG (1.5–100 μ m) and l‐NMMA (3–100 μ m) caused concentration‐related inhibition of the vasodilator effect of ACh (0.01–1.0 μ m) on the rabbit aorta without influencing responses to NP (0.03–0.5 μ m). l‐NOARG methyl ester (30 μ m) also inhibited ACh‐induced vasorelaxation with similar potency to NOARG. l‐arginine (30–150 μ m) but not d‐arginine (100 μ m) caused graded reversal of the inhibitory effect of both l‐NOARG (15 μ m) and l‐NMMA (30 μ m). Complete reversal of the effect of both inhibitors was achieved with 150 μ m l‐arginine. l‐Alanine (50 μ m), l‐arginosuccinic acid (5 μ m), l‐citrulline (50 μ m), l‐methionine (50 μ m) and l‐ornithine (50 μ m) failed to reverse the inhibitory effect of l‐NOARG (15 μ m). l‐NOARG (10–200 μ m) and l‐NMMA (30–100 μ m) inhibited the vasodilator effect of ACh (0.006–18.0 nmol) in the rat mesentery without affecting vasodilatation due to NP (1.1–11.1 nmol). l‐Arginine (100 μ m) but not d‐arginine (100 μ m) produced partial reversal of the effect of l‐NOARG (30 μ m) and l‐NMMA (30 μ m). l‐ and d‐N α‐butyloxycarbonyl N G‐nitro arginine (100 μ m) produced modest (approximately 20%) inhibition of the effect of ACh on the rabbit aorta; this effect was not reversible with l‐arginine (100 μ m). l‐N α‐monocarbobenzoxy arginine (l‐NMCA, 50 μ m), l‐N α‐N G‐dicarbobenzoxy arginine (l‐NDCA, 5 μ m) and l‐N G‐tosyl arginine (50 μ m) were inactive. These results identify l‐NOARG as a potent, l‐arginine reversible inhibitor of endothelium‐dependent vasodilatation. The available data suggests that l‐NOARG, like l‐NMMA, inhibits endothelial nitric oxide (NO) biosynthesis.