RT Journal Article SR Electronic T1 Local Anesthetic–Induced Inhibition of Human Neutrophil Priming: The Influence of Structure, Lipophilicity, and Charge JF Regional Anesthesia & Pain Medicine JO Reg Anesth Pain Med FD BMJ Publishing Group Ltd SP 9 OP 15 DO 10.1097/AAP.0b013e31827a3cbe VO 38 IS 1 A1 Susanne Picardi A1 Sibylle Cartellieri A1 Danja Groves A1 Klaus Hahnenekamp A1 Peter Gerner A1 Marcel E. Durieux A1 Markus F. Stevens A1 Philipp Lirk A1 Markus W. Hollmann YR 2013 UL http://rapm.bmj.com/content/38/1/9.abstract AB 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.