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Involvement of NO in the Endothelium-Independent Relaxing Effects of N ω -Hydroxy-l-arginine and Other Compounds Bearing a C=NOH Function in the Rat Aorta

2002; American Society for Pharmacology and Experimental Therapeutics; Volume: 303; Issue: 2 Linguagem: Inglês

10.1124/jpet.102.038612

1521-0103

Petr Vetrovsky, Jean‐Luc Boucher, Christa Schott, Petra Beranová, Karel Chalupský, Noëlle Callizot, Bernard Müller, G. Entlicher, Daniel Mansuy, Jean‐Claude Stoclet,

Inflammatory mediators and NSAID effects

The mechanisms of vasorelaxation elicited by N ω -hydroxy-l-arginine (l-NOHA) and other compounds bearing a C=NOH function and the structural determinants governing this effect were investigated in rat aorta. l-NOHA, formamidoxime, five aromatic monosubstituted amidoximes, and one aromatic monosubstituted ketoxime elicited relaxation in endothelium-denuded rings. N -Hydroxyguanidine and substituted N -hydroxyguanidines were markedly less active. Relaxations induced by l-NOHA and by the most active studied compound, 4-chlorobenzamidoxime (ClBZA), were unmodified by the presence of endothelium. In endothelium-denuded rings, they were blunted by the NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (300 μM) and by the inhibitor of guanylyl-cyclase activation 1 H [1,2,4,]oxadiazolo[4,3- a ]quinoxalin-1-one (1 μM). In addition, l-NOHA- and ClBZA both caused cGMP accumulation. l-Arginine, but notd-arginine (1 mM), antagonized the effect ofl-NOHA but not ClBZA. Both l-NOHA- and ClBZA-induced relaxations were inhibited by the NAD(P)H-dependent enzymes inhibitor diphenyliodonium (30 μM) and the NAD(P)H-dependent reductases inhibitor 7-ethoxyresorufin (10 μM), but they were unmodified by the cytochrome P450 (P450) inhibitor proadifen (10 μM) and by the NO synthase inhibitor N ω -nitro-l-arginine methyl ester (l-NAME, 300 μM). These results show thatl-NOHA and other compounds with a C=NOH function can cause endothelium-independent relaxation in the rat aorta. They suggest that activation of guanylyl cyclase and NO formation is implicated in relaxation and that a 7-ethoxyresorufin-sensitive NAD(P)H-dependent pathway is involved. On one hand, l-NOHA and amidoximes may be useful tools for characterizing this pathway in blood vessels and, on the other, may offer a novel approach for treating vascular diseases with impaired endothelial NO activity.