title: Local anesthetic-induced inhibition of human neutrophil priming: the influence of structure, lipophilicity, and charge.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anesthesiology, University Hospital Maastricht, The Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Picardi
authors.forename: Sibylle
authors.initials: S
authors.lastname: Cartellieri
authors.forename: Danja
authors.initials: D
authors.lastname: Groves
authors.forename: Klaus
authors.initials: K
authors.lastname: Hahnenkamp
authors.forename: Klaus
authors.initials: K
authors.lastname: Hahnenekamp
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Durieux
authors.forename: Markus F
authors.initials: MF
authors.lastname: Stevens
authors.forename: Philipp
authors.initials: P
authors.lastname: Lirk
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
mesh_terms: D000779:Anesthetics, Local / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009504:Neutrophils / Q000187:drug effects*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D013481:Superoxides