Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat.
BACKGROUND
Although ketamine has many beneficial effects in a rat model of noninfectious inflammation with lipopolysaccharide (LPS), its effects on gut ileus are unknown. We hypothesized that ketamine would improve LPS-induced ileus and therefore examined its effects on gastric emptying and intestinal transit as well as duodenogastric bile reflux and associated gastric bleeding.


METHODS
Male rats received saline or ketamine (7 mg/kg ip) 1 hour before saline or LPS (20 mg/kg ip) for 5 hours. Thirty minutes before killing, rats received orogastric rhodamine B isothiocyanate-labeled dextran and 5 minutes later fluorescein isothiocyanate-labeled dextran via a duodenal catheter. GI contents were collected for dye, bile acid, and hemoglobin (index of bleeding) determinations.


RESULTS
LPS significantly impaired intestinal transit and increased duodenogastric bile reflux and gastric luminal hemoglobin content. Ketamine improved intestinal transit, prevented LPS-induced bile reflux, and diminished gastric bleeding. In mechanistic studies, ketamine also attenuated LPS-induced upregulation of the proinflammatory genes inducible nitric oxide synthase and cyclo-oxygenase-2 in the stomach but preserved expression of the anti-inflammatory gene heme-oxygenase-1 (Western blot).


CONCLUSIONS
These data suggest that ketamine may prevent LPS-induced gastric bleeding by decreasing bile reflux through improved intestinal transit or by local changes in nitric oxide, prostaglandin, and carbon monoxide metabolism.
Ward
Jeremy L
JL
Department of Surgery, University of Texas Health Science Center, Houston, Texas 77030, USA.
Adams
Sasha D
SD
Delano
Benjamin A
BA
Clarke
Caroline
C
Radhakrishnan
Ravi S
RS
Weisbrodt
Norman W
NW
Mercer
David W
DW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004383:Duodenogastric Reflux / Q000139:chemically induced / Q000503:physiopathology*; D004926:Escherichia coli; D005746:Gastric Emptying / Q000187:drug effects; D005753:Gastric Mucosa / Q000378:metabolism; D005766:Gastrointestinal Contents / Q000737:chemistry; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology*; D005772:Gastrointestinal Transit / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006454:Hemoglobins / Q000032:analysis; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000893:Anti-Inflammatory Agents; D006454:Hemoglobins; D006993:Hypnotics and Sedatives; D008070:Lipopolysaccharides; D007649:Ketamine; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2