L-NG-NITRO ARGININE (L-NOARG), A NOVEL, L-ARGININE-REVERSIBLE INHIBITOR OF ENDOTHELIUM-DEPENDENT VASODILATATION INVITRO

1. 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). 2. L-NOARG (1.5-100 μM) and L-NMMA (3-100 μM) produced concentration-related contraction of the rabbit aorta precontracted with phenylephrine (700-900 nM). Similarly, L-NOARG (10-200 μM) and L-NMMA (30-100 μM) elevated perfusion pressure of the noradrenaline (NA, 0.6-2.5 mM)-preconstricted rat mesentery preparation. 3. L-NOARG (1.5-100 μM) and L-NMMA (3-100 μM) caused concentration-related inhibition of the vasodilator effect of ACh (0.01-1.0 μM) on the rabbit aorta without influencing responses to NP (0.03-0.5 μM). L-NOARG methyl ester (30 μM) also inhibited ACh-induced vasorelaxation with similar potency to NOARG. L-arginine (30-150 μM) but not D-arginine (100 μM) caused graded reversal of the inhibitory effect of both L-NOARG (15 μM) and L-NMMA (30 μM). Complete reversal of the effect of both inhibitors was achieved with 150 μM L-arginine. L-Alanine (50 μM), L-arginosuccinic acid (5 μM), L-citrulline (50 μM), L-methionine (50 μM) and L-ornithine (50 μM) failed to reverse the inhibitory effect of L-NOARG (15 μM). 4. L-NOARG (10-200 μM) and L-NMMA (30-100 μM) 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 μM) but not D-arginine (100 μM) produced partial reversal of the effect of L-NOARG (30 μM) and L-NMMA (30 μM). 5. L- and D-N(α)-butyloxycarbonyl N(G)-nitro arginine (100 μM) produced modest (approximately 20%) inhibition of the effect of ACh on the rabbit aorta; this effect was not reversible with L-arginine (100 μM). L-N(α)-monocarbobenzoxy arginine (L-NMCA, 50 μM), L-N(α)-N(G)-dicarbobenzoxy arginine (L-NDCA, 5 μM) and L-N(G)-tosyl arginine (50 μM) were inactive. 6 These results identify L-NOARG as a potent, L-arginine reversible inhibitor of endothelium-dependent vasodilatation. The available data suggest that L-NOARG, like L-NMMA, inhibits endothelial nitric oxide (NO) biosynthesis.