Effects of dexmedetomidine on regulating endotoxin-induced up-regulation of inflammatory molecules in murine macrophages.
BACKGROUND
Effects of dexmedetomidine on regulating endotoxin-induced upregulation of inflammatory molecules were elucidated.


METHODS
Murine macrophages (RAW264.7 cells) were treated with lipopolysaccharide (LPS, 100 ng/mL), LPS plus dexmedetomidine (0.01, 0.1, 1, 10, or 100 microM), LPS plus dexmedetomidine plus yohimbine, or LPS plus dexmedetomidine plus idazoxan. The dosages of dexmedetomidine were chosen to correspond to 1, 10, 100, and 1000 times of clinically relevant dosages (i.e., 0.01-0.1 microM). The levels of inducible nitric oxide synthase (iNOS)/nitric oxide (NO), cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-10 were measured.


RESULTS
Dexmedetomidine at 0.01 microM did not affect iNOS expression and NO production in activated macrophages. At 1 microM, dexmedetomidine significantly inhibited iNOS expression (up to 20.8% +/- 4.7%) and NO production (up to 26.2% +/- 6.8%). In contrast, dexmedetomidine at 100 microM significantly enhanced iNOS expression (up to 31.5% +/- 7.5%) and NO production (up to 34.9% +/- 5.6%). The effects of dexmedetomidine on COX-2 expression and the production of PGE2, TNF-alpha, IL-1beta, IL-6, and IL-10 paralleled the effects of dexmedetomidine on iNOS. Moreover, these effects were significantly reversed by both of the alpha2-adrenergic receptor antagonists, yohimbine, and idazoxan.


CONCLUSIONS
Dexmedetomidine at clinically relevant dosages did not significantly affect the expression of inflammatory molecules in activated macrophages. In contrast, dexmedetomidine at dosages higher than clinically relevant ones posted small but significant biphasic effects (inhibiting, then enhancing) on regulating the expression of inflammatory molecules, possibly through the alpha2-adrenergic receptors. However, as the magnitude of changes was relatively small, these effects may not be clinically significant.
Lai
Yen-Chun
YC
Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
Tsai
Pei-Shan
PS
Huang
Chun-Jen
CJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020927:Dexmedetomidine / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000316:Adrenergic alpha-Agonists; D016207:Cytokines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D020927:Dexmedetomidine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone