Peroxynitrite affects lidocaine by acting on membrane-constituting lipids

Inflammation frequently decreases local anesthetic effects, especially in dental anesthesia in patients with pulpitis and periodontitis. The pharmacokinetics and the mode of action of local anesthetics are closely associated with the hydrophobic interactions between these drugs and lipid bilayers that change the membrane physicochemical property, fluidity. A lipid oxidant, peroxynitrite, is produced by inflammatory cells, and it may act on nerve cell membranes and affect anesthetic efficacy. With respect to this speculated action, we addressed whether peroxynitrite acted on membrane-constituting lipids to decrease the membrane interactivity of lidocaine. Membrane fluidity changes were determined by measuring the fluorescence polarization of liposomes prepared with different phospholipids. Peroxynitrite (0.1-50 microM) rigidified nerve-cell model membranes consisting of unsaturated phospholipids, as well as liposomal membranes consisting of 1,2-dioleoylphosphatidylcholine and 1-stearoyl-2-arachidonylphosphatidylcholine, but peroxynitrite did not rigidify 1, 2-dipalmitoylphosphatidylcholine liposomal membranes. The pretreatment of nerve-cell model membranes with peroxynitrite (0.1-50 microM) decreased the membrane-fluidizing effects of lidocaine (5.0 mg x ml(-1)) to 63%-86% of the control (not treated with peroxynitrite) depending on the peroxynitrite concentration. As one of the mechanisms of the local anesthetic failure associated with inflammation, inflammatory peroxynitrite may affect local anesthesia by acting on membrane-constituting unsaturated phospholipids.