Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2.
BACKGROUND
Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury.


METHODS
Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS.


RESULTS
LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels.


CONCLUSIONS
These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.
Suliburk
James W
JW
Department of Surgery, The University of Texas Medical School at Houston, 77030, USA. James.W.Suliburk@uth.tmc.edu
Helmer
Kenneth S
KS
Gonzalez
Ernest A
EA
Robinson
Emily K
EK
Mercer
David W
DW
D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007530:Isoflurane / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000778:Anesthetics, Dissociative; D018685:Anesthetics, Inhalation; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D007649:Ketamine; D007530:Isoflurane; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases