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 albumin in the ileum and colon after 1 h, an effect reversed by the pretreatment with L-arginine (300 mg/kg, s.c.). Aminoguanidine (50 mg/kg, s.c.) also elevated arterial blood pressure over the 1 h investigation period. Similar acute potentiation of endotoxin-provoked vascular injury was observed 1 h following L-NMMA (50 mg/kg s.c.) which also increased blood pressure, indicating the inhibition of constitutive NO synthase. By contrast, administration of aminoguanidine (12.5-50 mg/kg, s.c.) 3 h after endotoxin, at the time of the expression of the inducible NO synthase, reduced the subsequent endotoxin-induced vascular leakage, as did L-NMMA (50 mg/kg). In homogenates of rat ileal or colonic tissue, aminoguanidine inhibited both the constitutive and inducible NO synthase activity showing only 2-fold selectivity for the inducible isoform. Thus, although aminoguanidine inhibits these isoforms of NO synthase, it is not a selective inhibitor of the inducible isoform in the intestinal microvasculature in vivo.