Increasing membrane interactions of local anaesthetics as hypothetic mechanism for their cardiotoxicity enhanced by myocardial ischaemia.
While myocardial ischaemia enhances the cardiotoxicity of local anaesthetics, the pharmacological background remains unclear. Cardiolipin (CL) localized in mitochondrial membranes is possibly the site of cardiotoxic action of local anaesthetics and peroxynitrite is produced by cardiac ischaemia and reperfusion. We verified the hypothetic mechanism that local anaesthetics may interact with CL-containing biomembranes to change the membrane biophysical property and their membrane interactions may be increased by peroxynitrite. Biomimetic membranes were prepared with different phospholipids and cholesterol of varying compositions. The membrane preparations were reacted with peroxynitrite of pathologically relevant concentrations and local anaesthetics (bupivacaine and lidocaine) of a cardiotoxic concentration separately or in combination. Changes in membrane fluidity were determined by measuring fluorescence polarization. Peroxynitrite decreased the fluidity of biomimetic membranes at 0.1-10 μM with the relative potency being CL>1-stearoyl-2-arachidonoylphosphatidylcholine>1,2-dipalmitoylphosphatidylcholine-constituting membranes, indicating the lipid peroxidation-induced membrane rigidification determined by the unsaturation degree of membrane lipids. When treated with 0.1-10 μM peroxynitrite, biomimetic membranes were more rigid with elevating the CL content from 0% to 30 mol%, suggesting that CL is a primary target of peroxynitrite. Bupivacaine and lidocaine fluidized at 200 μM biomimetic membranes containing 10 mol% CL and their effects were increased by pre-treating the membranes with 0.1 and 1 μM peroxynitrite. Cardiotoxic bupivacaine and lidocaine increasingly interact with CL-containing mitochondria model membranes which are relatively rigidified by peroxynitrite. Such an increasing membrane interaction may be, at least in part, responsible for the local anaesthetic cardiotoxicity enhanced by myocardial ischaemia.
Department of Dental Basic Education, Asahi University School of Dentistry, Mizuho, Japan. hiro@dent.asahi-u.ac.jp
Hironori
H
Tsuchiya
Maki
M
Mizogami
Kenji
K
Shigemi
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D000779:Anesthetics, Local / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002045:Bupivacaine / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002308:Cardiolipins / Q000737:chemistry / Q000378:metabolism*; D055598:Chemical Phenomena; D005454:Fluorescence Polarization; D006801:Humans; D008012:Lidocaine / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008560:Membrane Fluidity / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009994:Osmolar Concentration; D030421:Peroxynitrous Acid / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism
C462319:1-strearoyl-2-arachidonyl-sn-glycero-3-phosphatidylcholine; D000779:Anesthetics, Local; D002308:Cardiolipins; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D030421:Peroxynitrous Acid; D015060:1,2-Dipalmitoylphosphatidylcholine; D008012:Lidocaine; D002045:Bupivacaine