Peroxynitrite affects lidocaine by acting on membrane-constituting lipids

Abstract

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.

Increasing Membrane Interactions of Local Anaesthetics as Hypothetic Mechanism for Their Cardiotoxicity Enhanced by Myocardial Ischaemia

“…However, the present results do not necessarily agree with a previous study in which the membrane effect of lidocaine was decreased by reacting membrane lipids with inflammatory peroxynitrite . CL of a substantial amount was added for preparing mitochondria model membranes in the present study, whereas biomimetic membranes were previously prepared without CL to mimic peripheral nerve cell membranes.…”

“…In SAPC membranes as a nerve cell model membrane, the peroxynitrite‐induced membrane rigidification could influence nerve transmissions and membrane‐acting drug effects . Peroxynitrite produced by cardiac ischaemia and reperfusion peroxidizes membrane lipids, especially CL, with a subsequent membrane rigidification, thereby damaging cardiomyocyte mitochondrial membranes, resulting in the influence on cardiac functions .…”

Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

“…The following DPH fluorescence polarization measurements showed that the membrane-fluidizing effects of local anesthetics were inhibited by the peroxynitrite treatment. Such inhibitions are causable by peroxynitrite directly acting on anesthetic molecules [45] and indirectly on membrane lipids [46]. …”

“…The interaction of local anesthetics with peroxynitrite-treated membranes seems to relate to their cardiotoxic effects, not cardioprotective ones. The membrane interactivity of lidocaine was enhanced when mitochondria-mimetic membranes containing cardiolipin were pretreated with ischemic peroxynitrite, but reduced when nerve cell-mimetic membranes not containing cardiolipin were treated with inflammatory peroxynitrite [46], suggesting that the presence or absence of cardiolipin determines whether the membrane interaction of local anesthetics is increased or decreased.…”

Effectiveness of the addition of Lidocaine to a hemostatic, bioresorbable putty in the treatment of iliac crest donor site pain

“…In addition, the effects of lidocaine could have been also been altered by a local inflammatory response due to the surgical intervention and, additionally, to the putty. It has been postulated that inflammatory cell released peroxynitrite could decrease the effect of local anesthetic effects[ 26 , 27 ] . Our data do not suggest that the duration of pain relief was restricted by limited lidocaine release from the putty.…”