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Local Anesthetic–Induced Inhibition of Human Neutrophil Priming: The Influence of Structure, Lipophilicity, and Charge
  1. Susanne Picardi, MD*,
  2. Sibylle Cartellieri, MD*,
  3. Danja Groves, MD†,
  4. Klaus Hahnenekamp, MD‡,
  5. Peter Gerner, MD, PhD§,
  6. Marcel E. Durieux, MD, PhD*,
  7. Markus F. Stevens, MD, PhD∥,,
  8. Philipp Lirk, MD∥, and
  9. Markus W. Hollmann, MD, PhD*
  1. *Department of Anesthesiology, University Hospital Maastricht, the Netherlands; Departments of †Anesthesiology and ‡Anesthesiology and Critical Care, University Hospital Münster, Germany; §Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA; and ∥Department of Anesthesiology and ¶Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Academic Medical Center, Amsterdam, the Netherlands.
  1. Address correspondence to: Philipp Lirk, MD, Department of Anesthesiology, Academic Medical Center Amsterdam, PO Box 22600, 1105 DD Amsterdam, the Netherlands (e-mail: p.lirk{at}amc.uva.nl).

Abstract

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 α-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 Gαq-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.

https://doi.org/10.1097/AAP.0b013e31827a3cbe

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    Footnotes

    • Dr. Picardi is now with the Department of Anesthesiology, University Hospital Heidelberg, Germany, and Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Academic Medical Center, Amsterdam, the Netherlands. Dr. Cartellieri is now with the Department of Pediatrics, Clinical Center Kassel, Germany. Drs. Groves and Durieux are now with the Department of Anesthesiology, University of Virginia, Charlottesville, VA. Dr. Gerner is now with the Department of Anesthesiology, University of Salzburg, Austria. Dr. Hollmann is now with the Department of Anesthesiology and Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Academic Medical Center, Amsterdam, the Netherlands.

      This study was supported in part by an MD–medical research trainee grant from the Netherlands Organisation for Health Research and Development (ZonMW AGIKO to Dr. Picardi), by the Medical Faculty, University of Heidelberg, Germany (F206639), and by institutional funds from the Departments of Anesthesiology, University of Heidelberg, Germany, and Academic Medical Center, Amsterdam, the Netherlands.

      The authors declare no conflict of interest.

      The work should be attributed to the Departments of Anesthesiology, University of Heidelberg, Germany, and Academic Medical Center, Amsterdam, the Netherlands.

      Joseph M. Neal, MD, served as editor-in-chief for this article.

      Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.rapm.org).