Effects of ketamine/xylazine on expression of tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclo-oxygenase-2 in rat gastric mucosa during endotoxemia.
Some anesthetics attenuate expression of endotoxin-induced production of proinflammatory genes. The anesthetic combination of ketamine/xylazine (K/X) decreases lipopolysaccharide (LPS)-induced liver injury in rats. However, the effects of K/X on gut function and gene expression are unknown. The purpose of this study was to examine the effect of K/X on LPS-induced gastric fluid accumulation, and gastric tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), and cyclo-oxygenase (COX)-2 expression, as well as serum TNF-alpha protein levels over time. We hypothesized that K/X would attenuate these LPS-induced endpoints. Rats were given either intraperitoneal saline or K (70 mg/kg) and X (6 mg/kg) 1 h before saline or LPS (20 mg/kg i.p.) treatment of 1, 3, or 5 h. Serum and gastric fluid and mucosa were collected and TNF-alpha, iNOS, and COX-2 expression were determined. LPS caused a significant increase in early serum and gastric mucosal TNF-alpha protein expression at 1 h, an effect that was significantly attenuated by K/X pretreatment. LPS caused significant gastric stasis and increased iNOS and COX-2 mRNA expression and iNOS protein expression in the stomach when compared with controls. K/X attenuated LPS-induced gastric fluid accumulation and upregulation of iNOS mRNA and protein, but not COX-2. These data indicate that K/X inhibits some proinflammatory genes and pathophysiologic responses in the serum and stomach during endotoxemia. The effects of K/X appear to inhibit transcriptional events in iNOS expression, which may be dependent on K/X-induced inhibition of early TNF-alpha expression. Furthermore, in rat models of endotoxemia, especially those evaluating the stomach, careful consideration needs to be given if anesthetic combinations with ketamine and/or xylazine are used, as they alter LPS-induced responses.
Helmer
Kenneth S
KS
Department of Surgery, University of Texas Medical School, LBJ General Hospital, 5656 Kelley Street, Houston, TX 77026, USA.
Cui
Yan
Y
Chang
Lily
L
Dewan
Ashvin
A
Mercer
David W
DW
D000818:Animals; D051546:Cyclooxygenase 2; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014991:Xylazine / Q000494:pharmacology*
D007527:Isoenzymes; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014991:Xylazine; D007649:Ketamine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases