title: Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria.
abstract: BACKGROUND
  The authors previously reported that secondary carnitine deficiency may sensitize the heart to bupivacaine-induced arrhythmias. In this study, the authors tested whether bupivacaine inhibits carnitine metabolism in cardiac mitochondria.
  
  
  METHODS
  Rat cardiac interfibrillar mitochondria were prepared using a differential centrifugation technique. Rates of adenosine diphosphate-stimulated (state III) and adenosine diphosphate-limited (state IV) oxygen consumption were measured using a Clark electrode, using lipid or nonlipid substrates with varying concentrations of a local anesthetic.
  
  
  RESULTS
  State III respiration supported by the nonlipid substrate pyruvate (plus malate) is minimally affected by bupivacaine concentrations up to 2 mM. Lower concentrations of bupivacaine inhibited respiration when the available substrates were palmitoylcarnitine or acetylcarnitine; bupivacaine concentration causing 50% reduction in respiration (IC50 +/- SD) was 0.78+/-0.17 mM and 0.37+/-0.03 mM for palmitoylcarnitine and acetylcarnitine, respectively. Respiration was equally inhibited by bupivacaine when the substrates were palmitoylcarnitine alone, or palmitoyl-CoA plus carnitine. Bupivacaine (IC50 = 0.26+/-0.06 mM) and etidocaine (IC50 = 0.30+/-0.12 mM) inhibit carnitine-stimulated pyruvate oxidation similarly, whereas the lidocaine IC50 is greater by a factor of roughly 5, (IC50 = 1.4+/-0.26 mM), and ropivacaine is intermediate, IC50 = 0.5+/-0.28 mM.
  
  
  CONCLUSIONS
  Bupivacaine inhibits mitochondrial state III respiration when acylcarnitines are the available substrate. The substrate specificity of this effect rules out bupivacaine inhibition of carnitine palmitoyl transferases I and II, carnitine acetyltransferase, and fatty acid beta-oxidation. The authors hypothesize that differential inhibition of carnitine-stimulated pyruvate oxidation by various local anesthetics supports the clinical relevance of inhibition of carnitine-acylcarnitine translocase by local anesthetics with a cardiotoxic profile.
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine at Chicago, 60612, USA. guyw@uic.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Weinberg
authors.forename: J W
authors.initials: JW
authors.lastname: Palmer
authors.forename: T R
authors.initials: TR
authors.lastname: VadeBoncouer
authors.forename: M B
authors.initials: MB
authors.lastname: Zuechner
authors.forename: G
authors.initials: G
authors.lastname: Edelman
authors.forename: C L
authors.initials: CL
authors.lastname: Hoppel
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D002331:Carnitine / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
chemical_list: D000779:Anesthetics, Local; D000244:Adenosine Diphosphate; D019289:Pyruvic Acid; D002331:Carnitine; D002045:Bupivacaine