AMINOGUANIDINE SELECTIVELY INHIBITS INDUCIBLE NITRIC-OXIDE SYNTHASE

1 Endotoxin induces nitric oxide synthase in vascular tissue, includin g rat main pulmonary artery. Currently available agents that cause inh ibition of nitric oxide synthase are relatively non-selective between the constitutive and inducible forms of the enzyme. 2 Aminoguanidine c aused a dose-dependent increase in phenylephrine-induced tension in in tact and endothelium-denuded pulmonary artery rings from endotoxin-tre ated rats, but had no effect on sham-treated controls. 3 Contraction c aused by aminoguanidine in endothelium-denuded vessels from endotoxin- treated rats was unaffected by indomethacin (10 muM), and by cimetidin e and mepyramine (both 10 muM), excluding an effect of aminoguanidine mediated by arachidonic acid metabolites or histamine. 4 Contraction c aused by aminoguanidine in endothelium-denuded vessels from endotoxin- treated rats was abolished by L-arginine (2 mM) and L-N(G)-monomethyl arginine (300 muM), but unaffected by D-arginine and D-N(G)-monomethyl arginine, suggesting that its action is mediated by the L-arginine/ni tric oxide pathway. 5 Aminoguanidine had no effect on acetylcholine-in duced relaxation of intact vessels from sham-treated rats. However, re laxation of artery rings from endotoxin-treated rats by L-arginine was competitively inhibited by aminoguanidine. 6 These results in isolate d main pulmonary arteries of the rat confirm previous reports that ami noguanidine is a selective inhibitor of inducible nitric oxide synthas e.