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Cardiolipin (<jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>) 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 <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>\u2010containing 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\u201310\u00a0\u03bcM with the relative potency being <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>&gt;1\u2010stearoyl\u20102\u2010arachidonoylphosphatidylcholine&gt;1,2\u2010dipalmitoylphosphatidylcholine\u2010constituting membranes, indicating the lipid peroxidation\u2010induced membrane rigidification determined by the unsaturation degree of membrane lipids. When treated with 0.1\u201310\u00a0\u03bcM peroxynitrite, biomimetic membranes were more rigid with elevating the <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content> content from 0% to 30\u00a0mol%, suggesting that <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content> is a primary target of peroxynitrite. Bupivacaine and lidocaine fluidized at 200\u00a0\u03bcM biomimetic membranes containing 10\u00a0mol% <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content> and their effects were increased by pre\u2010treating the membranes with 0.1 and 1\u00a0\u03bcM peroxynitrite. Cardiotoxic bupivacaine and lidocaine increasingly interact with <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>\u2010containing 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.<\/jats:p>","DOI":"10.1111\/j.1742-7843.2012.00909.x","type":"journal-article","created":{"date-parts":[[2014,10,21]],"date-time":"2014-10-21T11:06:52Z","timestamp":1413889612000},"page":"303-308","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Increasing Membrane Interactions of Local Anaesthetics as Hypothetic Mechanism for Their Cardiotoxicity Enhanced by Myocardial Ischaemia"],"prefix":"10.1111","volume":"111","author":[{"given":"Hironori","family":"Tsuchiya","sequence":"first","affiliation":[{"name":"Department of Dental Basic Education Asahi University School of Dentistry  Mizuho Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Mizogami","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and 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