RT Journal Article
SR Electronic
T1 Involvement of NO in the Endothelium-Independent Relaxing Effects of <em>N</em>
<sup>ω</sup>-Hydroxy-<span class="sc">l</span>-arginine and Other Compounds Bearing a C=NOH Function in the Rat Aorta
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 823
OP 830
DO 10.1124/jpet.102.038612
VO 303
IS 2
A1 Petr Vetrovsky
A1 Jean-Luc Boucher
A1 Christa Schott
A1 Petra Beranova
A1 Karel Chalupsky
A1 Noëlle Callizot
A1 Bernard Muller
A1 Gustav Entlicher
A1 Daniel Mansuy
A1 Jean-Claude Stoclet
YR 2002
UL http://jpet.aspetjournals.org/content/303/2/823.abstract
AB The mechanisms of vasorelaxation elicited byNω-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 substitutedN-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 1H[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 inhibitorNω-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. The American Society for Pharmacology and Experimental Therapeutics