Role of nitric oxide in hypoxia-induced colonic dysfunction in the neonatal rat.
In addition to being an important mediator in the regulation of intestinal integrity, nitric oxide (NO), when produced in large quantities by the inducible isoform of NO synthase, can also be cytotoxic. The aim of this study was to examine the role of NO in hypoxia-induced colonic injury in neonatal rats. Rats (10-12 days old) were exposed to a hypoxic environment of 14% O2-86% N2 for 30 min. NO synthase activity in colonic tissue was measured via the conversion of L-[14C]arginine to L-[14C]citrulline. Epithelial permeability was assessed by measuring the plasma-to-lumen flux of [3H]mannitol or the luminal protein content of colonic lavage. The role of neutrophils was assessed by pretreatment with antineutrophil serum (200 microl/kg ip) and measurement of tissue myeloperoxidase activity. Hypoxia resulted in an elevation in the activity of the inducible Ca2+-independent isoform of NO synthase in colonic tissue, which was maximal between 4 and 6 h posthypoxia and was associated with an increase in myeloperoxidase activity, [3H]mannitol flux, luminal protein content, and histological damage. These effects were attenuated by pretreatment with dexamethasone or the NO synthase inhibitors aminoguanidine and N(G)-nitro-L-arginine methyl ester, whereas the inactive stereoisomer N(G)-nitro-D-arginine methyl ester was without effect. Pretreatment with antineutrophil serum significantly reduced circulating neutrophils, myeloperoxidase activity, and Ca2+-independent NO synthase activity. These findings demonstrate that hypoxia-induced colonic injury in neonatal rats is associated with elevated NO synthase activity, which is related to an increase in neutrophil infiltration.
Brown
J F
JF
Department of Physiology, Faculty of Medicine, University of Western Ontario, London, Canada.
Tepperman
B L
BL
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010539:Permeability; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011506:Proteins; D009569:Nitric Oxide; D008353:Mannitol; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester