AMINOGUANIDINE INHIBITS BOTH CONSTITUTIVE AND INDUCIBLE NITRIC-OXIDE SYNTHASE ISOFORMS IN RAT INTESTINAL MICROVASCULATURE IN-VIVO

The effects of aminoguanidine on the intestinal vascular permeability following endotoxin administration in vivo has been compared to those of the nitric oxide (NO) synthase inhibitor N-G-monomethyI-L-arginine (L-NMMA) in the rat. Concurrent administration of aminoguanidine. (12. 5-50 mg/kg, s.c.) with endotoxin (E. coli lipopolysaccharide, 3 mg/kg, i.v.), dose dependently increased vascular leakage of radiolabelled a lbumin in the ileum and colon after 1 h, an effect reversed by the pre treatment with L-arginine (300 mg/kg, s.c.). Aminoguanidine (50 mg/kg, s.c.) also elevated arterial blood pressure over the 1 h investigatio n period. Similar acute potentiation of endotoxin-provoked vascular in jury was observed 1 h following L-NMMA (50 mg/kg s.c.) which also incr eased blood pressure, indicating the inhibition of constitutive NO syn thase. By contrast, administration of aminoguanidine (12.5-50 mg/kg, s .c.) 3 h after endotoxin, at the time of the expression of the inducib le NO synthase, reduced the subsequent endotoxin-induced vascular leak age, as did L-NMMA (50 mg/kg). In homogenates of rat ileal or colonic tissue, aminoguanidine inhibited both the constitutive and inducible N O synthase activity showing only 2-fold selectivity for the inducible isoform. Thus, although aminoguanidine inhibits these isoforms of NO s ynthase, it is not a selective inhibitor of the inducible isoform in t he intestinal microvasculature in vivo.