Increasing membrane interactions of local anaesthetics as hypothetic mechanism for their cardiotoxicity enhanced by myocardial ischaemia.

摘要: While myocardial ischaemia enhances the cardiotoxicity of local anaesthetics, pharmacological background remains unclear. Cardiolipin (CL) localized in mitochondrial membranes is possibly site cardiotoxic action anaesthetics and peroxynitrite produced by cardiac reperfusion. We verified hypothetic mechanism that may interact with CL-containing biomembranes to change membrane biophysical property their interactions be increased peroxynitrite. Biomimetic were prepared different phospholipids cholesterol varying compositions. The preparations reacted pathologically relevant concentrations (bupivacaine lidocaine) a concentration separately or combination. Changes fluidity determined measuring fluorescence polarization. Peroxynitrite decreased biomimetic at 0.1-10 μM relative potency being CL>1-stearoyl-2-arachidonoylphosphatidylcholine>1,2-dipalmitoylphosphatidylcholine-constituting membranes, indicating lipid peroxidation-induced rigidification unsaturation degree lipids. When treated peroxynitrite, more rigid elevating CL content from 0% 30 mol%, suggesting primary target Bupivacaine lidocaine fluidized 200 μM containing 10 mol% effects pre-treating 0.1 1 μM Cardiotoxic bupivacaine increasingly mitochondria model which are relatively rigidified Such an increasing interaction be, least part, responsible for anaesthetic enhanced ischaemia.