Involvement of NO in the endothelium-independent relaxing effects of N(omega)-hydroxy-L-arginine and other compounds bearing a C=NOH function in the rat aorta.
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.
Vetrovsky
Petr
P
Pharmacology and Physico-Chemistry, Centre National de la Recherche Scientifique (Unité Mixte Recherche 7034) and University Louis Pasteur, Strasbourg, France.
Boucher
Jean-Luc
JL
Schott
Christa
C
Beranova
Petra
P
Chalupsky
Karel
K
Callizot
Noëlle
N
Muller
Bernard
B
Entlicher
Gustav
G
Mansuy
Daniel
D
Stoclet
Jean-Claude
JC
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D027701:Organic Cation Transport Proteins; D010069:Oxadiazoles; D011810:Quinoxalines; D009569:Nitric Oxide; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D009251:NADPH-Ferrihemoprotein Reductase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester