ACTIONS OF ISOFORM-SELECTIVE AND NONSELECTIVE NITRIC-OXIDE SYNTHASE INHIBITORS ON ENDOTOXIN-INDUCED VASCULAR LEAKAGE IN RAT COLON

The effects of the nitric oxide (NO) synthase inhibitor, N-(3-(aminome thyl)benzyl)-acetamidine (1400W) which is selective for the inducible isoform of NO synthase, on rat colonic microvascular injury provoked b y Escherichia coli endotoxin (3 mg/kg i.v.) has been compared to those of aminoguanidine (25-50 mg/kg, s.c.), N-G-iminoethyl-L-ornithine (L- NIO, 15-30 mg/kg, s.c.) and N-G-nitro-L-arginine methyl ester (L-NAME, 2-5 mg/kg, s.c.). Administration of aminoguanidine, L-NIO or L-NAME c oncurrently with endotoxin provoked microvascular albumin leakage 1 h later, presumably by inhibiting constitutive NO synthase, whereas 1400 W(0.1-10 mg/kg, s.c.) had no such effect. Administration of all these agents during the expression of inducible NO synthase (i.e. 3 h after endotoxin challenge) attenuated the subsequent endotoxin-provoked albu min leakage I h later. Moreover, concurrent administration of 1400W (0 .2-5 mg/kg, s.c.; doses that did not affect systemic arterial blood pr essure) with endotoxin suppressed the subsequent rise in albumin leaka ge after 5 h. These findings indicate that 1400W is a potent inhibitor of colonic microvascular injury associated with induction of NO synth ase in vivo. 1400W will thus be useful to investigate in vivo the ther apeutic potential of a selective inducible NO synthase inhibitor in in flammation. (C) 1997 Elsevier Science B.V.