title: Dissociation of the vacuolar and macroautophagic cytopathology from the cytotoxicity induced by the lipophilic local anesthetic bupivacaine.
abstract: Local anesthetics, like many other cationic drugs, induce a vacuolar and macroautophagic cytopathology that has been observed in vivo and in various cell types; some also induce cytotoxicity of mitochondrial origin (apoptosis and necrosis) and it is not known whether the 2 types of toxicity overlap or interact. We compared bupivacaine with a more hydrophilic agent, lidocaine, for morphological, functional, and toxicological responses in a previously exploited nonneuronal system, primary smooth muscle cells. Bupivacaine induced little vacuolization (≥2.5 mmol/L, 4 h), but elicited autophagic accumulation (≥0.5 mmol/L, 4 h) and was massively cytotoxic at 2.5-5 mmol/L (4-24 h), the latter effect being unabated by the V-ATPase inhibitor bafilomycin A1. Lidocaine exerted little cytotoxicity at and below 5 mmol/L for 24 h, but intensely induced the V-ATPase-dependent vacuolar and autophagic cytopathology. Bupivacaine was more potent than lidocaine in disrupting mitochondrial potential, as judged by Mitotracker staining (significant proportions of cells affected in the 1-5 and 5-10 mmol/L concentration ranges, respectively). The addition of mitochondrial-inactivating toxins antimycin A and oligomycin to lidocaine (2.5 mmol/L) reproduced the profile of bupivacaine action (low intensity of vacuolization and retained autophagic accumulation). The high potency of bupivacaine as a mitochondrial toxicant eclipses the benign vacuolar and autophagic response seen with more hydrophilic local anesthetics.
authors.affiliation: Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Morissette
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bawolak
authors.forename: François
authors.initials: F
authors.lastname: Marceau
mesh_terms: D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D002045:Bupivacaine / Q000633:toxicity*; D002478:Cells, Cultured; D008012:Lidocaine / Q000633:toxicity; D018942:Macrolides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009840:Oligomycins / Q000494:pharmacology; D011817:Rabbits; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D018942:Macrolides; D009840:Oligomycins; D000968:Antimycin A; C040929:bafilomycin A1; D008012:Lidocaine; D025262:Vacuolar Proton-Translocating ATPases; D002045:Bupivacaine