title: Myocardial accumulation of bupivacaine and ropivacaine is associated with reversible effects on mitochondria and reduced myocardial function.
abstract: BACKGROUND
  Mechanisms of local anesthetic cardiac toxicity are still not completely understood. In this study, we analyzed whether concentrations of local anesthetics found in clinical toxicity affect myocardial mitochondrial structure and oxygen consumption.
  
  
  METHODS
  Guinea pig isolated heart Langendorff preparations were exposed to bupivacaine (3.0 and 7.5 μg/mL) and ropivacaine (3.6 and 9.0 μg/mL) for 10 minutes. Heart rate, systolic blood pressure, the first derivative of left ventricular pressure (+dP/dt), electrocardiogram, and coronary flow were recorded. The local anesthetic tissue concentration was measured either immediately after local anesthetic exposure, or after 20- and 60-minute washout periods. In addition, electron microscopy of myocardial mitochondria was performed using a scoring system for structural damage of mitochondria. Cardiomyocyte cell culture was incubated with bupivacaine, and oxygen consumption ratio, extracellular acidification, and relative amounts of PGC-1α mRNA, a regulator of cellular energy metabolism, were determined.
  
  
  RESULTS
  Bupivacaine and ropivacaine induced reversible PR interval and QRS prolongation, and left ventricular pressure and +dP/dt reduction. Myocardial tissue concentration of local anesthetics was 3-fold the arterial concentration. Mitochondria showed a significant concentration-dependent morphological swelling after local anesthetic application. These changes were reversed by a 20-minute washout period for ropivacaine and by a 60-minute washout for bupivacaine. Bupivacaine reduced mitochondrial oxygen consumption and increased PGC-1α expression in neonatal cardiomyocyte cell cultures, whereas fatty acid metabolism remained unaffected.
  
  
  CONCLUSIONS
  Bupivacaine and ropivacaine accumulate in the myocardium. Reversible local anesthetic-induced mitochondrial swelling occurs at concentrations that induce a negative inotropic effect. Bupivacaine reduces cellular metabolism, whereas this reduction is reversible by fatty acids. Interaction with mitochondria may contribute to the negative inotropic effect of local anesthetics.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Dresden, Dresden, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hiller
authors.forename: Peter
authors.initials: P
authors.lastname: Mirtschink
authors.forename: Christine
authors.initials: C
authors.lastname: Merkel
authors.forename: Lilla
authors.initials: L
authors.lastname: Knels
authors.forename: Reinhard
authors.initials: R
authors.lastname: Oertel
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
authors.forename: Thea
authors.initials: T
authors.lastname: Koch
authors.forename: Sebastian N
authors.initials: SN
authors.lastname: Stehr
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000009:adverse effects* / Q000378:metabolism*; D000779:Anesthetics, Local / Q000009:adverse effects* / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002045:Bupivacaine / Q000009:adverse effects* / Q000378:metabolism*; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077212:Ropivacaine; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D000077212:Ropivacaine; D000255:Adenosine Triphosphate; D002045:Bupivacaine