期刊
REGIONAL ANESTHESIA AND PAIN MEDICINE
卷 38, 期 1, 页码 9-15出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/AAP.0b013e31827a3cbe
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资金
- Netherlands Organisation for Health Research and Development (ZonMW AGIKO)
- Medical Faculty, University of Heidelberg, Germany [F206639]
- Department of Anesthesiology, University of Heidelberg, Germany
- Department of Anesthesiology, Academic Medical Center, Amsterdam, the Netherlands
Background and Objectives: Local anesthetics (LAs) are widely known for inhibition of voltage-gated sodium channels underlying their antiarrhythmic and antinociceptive effects. However, LAs have significant immunomodulatory properties and were shown to affect human neutrophil functions independent of sodium-channel blockade. Previous studies suggest a highly selective interaction between LAs and the alpha-subunit of G protein-coupled receptors of the Gq/G11 family as underlying mechanism. Providing a detailed structure function analysis, this study aimed to determine the active parts within the LA molecule responsible for the effects on human neutrophil priming. Methods: Human neutrophils were incubated with structurally different LAs for 60 minutes, followed by priming and activation using either platelet-activating factor or lysophosphatidic acid and N-formyl-methionyl-L-leucyl-L-phenylalanine. Superoxide anion generation was determined, using the cytochrome c reduction assay. Results: Differences in priming inhibition of human neutrophils between LAs were smaller than expected, although significant. Ester-linked LAs blocked priming responses more effectively than did amide LAs. Furthermore, the inhibitory potency of LAs on priming decreased with an increase of their respective octanol-buffer coefficient, and inhibition did not correlate with sodium-channel-blocking potency. Charge was not crucially required for priming inhibition, yet it played a role in effect size. Conclusions: Local anesthetics significantly attenuated G alpha q-protein-mediated neutrophil priming. The most potent inhibition was achieved by ester compounds, inversely correlated with their octanol-buffer coefficient, and enhanced by permanent charges within the LA molecule. No correlation to their potency of blocking sodium channels was found. (Reg Anesth Pain Med 2013;38: 9-15)
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