Actions of isoform-selective and non-selective nitric oxide synthase inhibitors on endotoxin-induced vascular leakage...

The effects of the nitric oxide (NO) synthase inhibitor, N-(3-(aminomethyl)benzyl)-acetamidine (1400W) which is selective for the inducible isoform of NO synthase, on rat colonic microvascular injury provoked by Escherichia coli endotoxin (3 mg/kg i.v.) has been compared to those of aminoguanidine (25-50 mg/kg, s.c.), NG-iminoethyl-L-ornithine (L-NIO, 15-30 mg/kg, s.c.) and NG-nitro-L-arginine methyl ester (L-NAME, 2-5 mg/kg, s.c.). Administration of aminoguanidine, L-NIO or L-NAME concurrently with endotoxin provoked microvascular albumin leakage 1 h later, presumably by inhibiting constitutive NO synthase, whereas 1400W (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 albumin leakage 1 h later. Moreover, concurrent administration of 1400W (0.2-5 mg/kg, s.c.; doses that did not affect systemic arterial blood pressure) with endotoxin suppressed the subsequent rise in albumin leakage after 5 h. These findings indicate that 1400W is a potent inhibitor of colonic microvascular injury associated with induction of NO synthase in vivo. 1400W will thus be useful to investigate in vivo the therapeutic potential of a selective inducible NO synthase inhibitor in inflammation.