Local anesthetic effects on priming and activation of human neutrophils

Background: Local anesthetics (LAs) have been shown to inhibit human polymo rphonuclear neutrophil (hPMN) functions in vitro, but mechanisms are poorly understood. In this study the authors determined how LAs affect superoxide anion production of hPMNs primed with platelet-activating factor (PAF), Th e authors studied which pharmacologic properties of LAs are important for t his action and assessed the LA site of action within the PAF signaling path way. Methods: Metabolic activity of primed and/or activated hPMNs were measured using the cytochrome-c assay. hPMNs were incubated with several LAs for 1 h to assess interference with PAL signaling, Using protein kinase C (PKC) in hibitors, the PKC activator phorbol myristate acetate (PMA), and the phosph olipase C (PLC) antagonist U-73122, we studied involvement of PKC and PLC i n the priming process. Pertussis toxin (PTX) was used to characterize the G proteins mediating this pathway. Combined administration of lidocaine with PMA or PTX was used to determine the LA site of action within the priming pathway. Results: Platelet-activating factor effectively primed hPMNs, Ester LAs (te tracaine and benzocaine) exerted the most profound inhibitory effect on PAF -primed hPMNs, whereas inhibitory potency of amide LAs increased with decre ased charged fraction. The major PAF-induced priming pathway is PLC- and PK C-dependent and mainly G(q)-mediated, The main target site for LA In this p athway is located upstream of PKC. Conclusions: Local anesthetics in clinically relevant concentrations inhibi t superoxide anion production of PAL-primed hPMNs, Effects on priming by th ese compounds might explain, at least in part, the previously unexplained d ifference between concentrations of LAs required for their antiinflammatory action in vitro and in vivo. This study suggests a target site for LAs wit hin a G(q)-coupled signaling pathway.