Nomega-hydroxy-L-arginine homologues and hydroxylamine as nitric oxide-dependent vasorelaxant agents.
Endothelium-independent relaxant activities of N(omega)-hydroxy-L-arginine (L-NOHA) homologues and hydroxylamine, a possible intermediate in nitric oxide (NO) formation, were examined in rat aortic rings. Addition of one -CH(2)- group to the -(CH(2))(x)- chain between the alpha-amino acid and the hydroxyguanidine group (x=4) almost abolished-while deletion of one or two -CH(2)- (x=1 or 2) enhanced-the relaxant activity of L-NOHA homologues. N(omega)-hydroxy-nor-L-arginine- (x=2) and hydroxylamine-induced relaxations were blunted by a NO scavenger and by inhibitors of the guanylyl cyclase pathway, but not by NO synthase or cytochrome P(450) inhibitors (except 7-ethoxyresorufin). However, aortic NO formation was detected (using electron paramagnetic resonance) in the presence of concentrations of these compounds higher than those producing relaxation. These findings support the view that endothelium-independent vasorelaxations induced by both L-NOHA homologues with a required chain length x</=3 and hydroxylamine are mediated by NO-dependent activation of guanylyl cyclase, through a 7-ethoxyresorufin-inhibited mechanism.
Beranova
Petra
P
Pharmacology and Physico-Chemistry, Centre National de la Recherche Scientifique and University Louis Pasteur of Strasbourg, Unité Mixte de Recherche 7034, Illkirch, France.
Chalupsky
Karel
K
Kleschyov
Andrei L
AL
Schott
Christa
C
Boucher
Jean-Luc
JL
Mansuy
Daniel
D
Munzel
Thomas
T
Muller
Bernard
B
Stoclet
Jean-Claude
JC
D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D019811:Hydroxylamine / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010069:Oxadiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D019811:Hydroxylamine; D009569:Nitric Oxide; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester