Aminoguanidine inhibits both constitutive and inducible nitric oxide synthase isoforms in rat intestinal microvasculature in vivo.
The effects of aminoguanine on the intestinal vascular permeability following endotoxin administration in vivo has been compared to those of the nitric oxide (NO) synthase inhibitor NG-monomethyl-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.
Laszlo
F
F
Wellcome Foundation Ltd., Beckenham, Kent, UK.
Evans
S M
SM
Whittle
B J
BJ
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019001:Nitric Oxide Synthase; D051381:Rats; D017208:Rats, Wistar; D019323:omega-N-Methylarginine
D006146:Guanidines; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine