Does upregulation of inducible nitric oxide synthase (iNOS) render the stomach more susceptible to damage?
Nitric oxide from constitutive nitric oxide synthase (NOS) augments gastric mucosal blood flow and is important in mucosal defense. However, the function of the inducible isoform of NOS (iNOS) in the gastric mucosa remains to be fully elucidated. This study was done to examine the role of iNOS in gastric mucosal blood flow and gastric injury following endotoxemia. Conscious rats were given intraperitoneal saline or lipopolysaccharide (LPS, 5 or 20 mg/kg). Five hours later, rats were anesthetized, a laparotomy made, gastric fluid aspirated, and 3 ml of 20% ethanol introduced into the forestomach. Rats were sacrificed 10 min later for assessment of macroscopic injury (mm2) to the gastric mucosa. Other rats did not receive 20% ethanol, but instead, gastric mucosal blood flow was determined with laser Doppler, followed by sacrifice and removal of stomachs for determination of gastric mucosal iNOS immunoreactivity (Western immunoblot). Lipopolysaccharide dose dependently increased gastric injury, decreased gastric mucosal blood flow, and increased gastric mucosal iNOS immunoreactivity compared to rats receiving saline. In additional experiments and using a similar protocol, intraperitoneal administration of aminoguanidine (45 mg/kg), an iNOS inhibitor, reversed lipopolysaccharide-induced gastric injury and restored gastric mucosal blood flow to baseline, whereas the nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (5 mg/kg) did not. Taken together, these data suggest that upregulation of iNOS is in part responsible for the detrimental effects of LPS on the gastric mucosa, possibly from a reduction in gastric mucosal blood flow.
Castañeda
A A
AA
Department of Surgery, University of Texas-Houston Medical School, Houston, Texas, 77030, USA.
Denning
J W
JW
Chang
L
L
Mercer
D W
DW
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019446:Endotoxemia / Q000201:enzymology* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000098:blood supply*; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013270:Stomach / Q000201:enzymology* / Q000473:pathology*
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D000431:Ethanol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine