Involvement of NO in the Endothelium-Independent Relaxing Effects ofNω-Hydroxy-l-arginine and Other Compounds Bearing a C=NOH Function in the Rat Aorta
| Autor: | Noëlle Callizot, Petra Beranova, Karel Chalupsky, Christa Schott, Jean-Claude Stoclet, Bernard Muller, Jean-Luc Boucher, G. Entlicher, Petr Vetrovsky, Daniel Mansuy |
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| Rok vydání: | 2002 |
| Předmět: |
Male
Nitric Oxide Synthase Type III Organic Cation Transport Proteins Arginine Endothelium Stereochemistry Muscle Relaxation Aorta Thoracic In Vitro Techniques Nitric Oxide Muscle Smooth Vascular Scavenger chemistry.chemical_compound Quinoxalines medicine.artery medicine Animals Enzyme Inhibitors Rats Wistar Cyclic GMP NADPH-Ferrihemoprotein Reductase Pharmacology chemistry.chemical_classification Oxadiazoles Aorta biology Cytochrome P450 Rats Proadifen NG-Nitroarginine Methyl Ester Enzyme medicine.anatomical_structure chemistry Guanylate Cyclase biology.protein Molecular Medicine Indicators and Reagents Endothelium Vascular NAD+ kinase Nitric Oxide Synthase |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 303:823-830 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | The mechanisms of vasorelaxation elicited by N(omega)-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 microM) and by the inhibitor of guanylyl-cyclase activation 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (1 microM). In addition, L-NOHA- and ClBZA both caused cGMP accumulation. L-Arginine, but not D-arginine (1 mM), antagonized the effect of L-NOHA but not ClBZA. Both L-NOHA- and ClBZA-induced relaxations were inhibited by the NAD(P)H-dependent enzymes inhibitor diphenyliodonium (30 microM) and the NAD(P)H-dependent reductases inhibitor 7-ethoxyresorufin (10 microM), but they were unmodified by the cytochrome P450 (P450) inhibitor proadifen (10 microM) and by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 300 microM). These results show that L-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. |
| Databáze: | OpenAIRE |
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