Aminoguanidine selectively inhibits inducible nitric oxide synthase.
1. Endotoxin induces nitric oxide synthase in vascular tissue, including rat main pulmonary artery. Currently available agents that cause inhibition of nitric oxide synthase are relatively non-selective between the constitutive and inducible forms of the enzyme. 2. Aminoguanidine caused a dose-dependent increase in phenylephrine-induced tension in intact and endothelium-denuded pulmonary artery rings from endotoxin-treated rats, but had no effect on sham-treated controls. 3. Contraction caused by aminoguanidine in endothelium-denuded vessels from endotoxin-treated rats was unaffected by indomethacin (10 microM), and by cimetidine and mepyramine (both 10 microM), excluding an effect of aminoguanidine mediated by arachidonic acid metabolites or histamine. 4. Contraction caused by aminoguanidine in endothelium-denuded vessels from endotoxin-treated rats was abolished by L-arginine (2 mM) and L-NG-monomethyl arginine (300 microM), but unaffected by D-arginine and D-NG-monomethyl arginine, suggesting that its action is mediated by the L-arginine/nitric oxide pathway. 5. Aminoguanidine had no effect on acetylcholine-induced relaxation of intact vessels from shamtreated rats. However, relaxation of artery rings from endotoxin-treated rats by L-arginine was competitively inhibited by aminoguanidine.6. These results in isolated main pulmonary arteries of the rat confirm previous reports that aminoguanidine is a selective inhibitor of inducible nitric oxide synthase.
Griffiths
M J
MJ
Department of Thoracic Medicine, National Heart & Lung Institute, London.
Messent
M
M
MacAllister
R J
RJ
Evans
T W
TW
D000109:Acetylcholine / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology; D004731:Endotoxins / Q000494:pharmacology; D004790:Enzyme Induction; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D019001:Nitric Oxide Synthase; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019323:omega-N-Methylarginine
D004731:Endotoxins; D006146:Guanidines; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D002927:Cimetidine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011738:Pyrilamine; D000109:Acetylcholine; C004479:pimagedine; D007213:Indomethacin