Myocardial accumulation of bupivacaine and ropivacaine is associated with reversible effects on mitochondria and reduced myocardial function
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Myocardial accumulation of bupivacaine and ropivacaine is associated with reversible effects on mitochondria and reduced myocardial function. / Hiller, Nicole; Mirtschink, Peter; Merkel, Christine; Knels, Lilla; Oertel, Reinhard; Christ, Torsten; Deussen, Andreas; Koch, Thea; Stehr, Sebastian N.
In: ANESTH ANALG, Vol. 116, No. 1, 01.01.2013, p. 83-92.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Myocardial accumulation of bupivacaine and ropivacaine is associated with reversible effects on mitochondria and reduced myocardial function
AU - Hiller, Nicole
AU - Mirtschink, Peter
AU - Merkel, Christine
AU - Knels, Lilla
AU - Oertel, Reinhard
AU - Christ, Torsten
AU - Deussen, Andreas
AU - Koch, Thea
AU - Stehr, Sebastian N
N1 - Christ für: Univ Hosp Dresden, Dept Pharmacol & Toxicol, Dresden, Germany
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Adenosine Triphosphate
KW - Amides
KW - Anesthetics, Local
KW - Animals
KW - Animals, Newborn
KW - Bupivacaine
KW - Cells, Cultured
KW - Coronary Circulation
KW - Extracellular Space
KW - Guinea Pigs
KW - Mice
KW - Microscopy, Electron, Transmission
KW - Mitochondria, Heart
KW - Myocardial Contraction
KW - Myocardium
KW - Myocytes, Cardiac
KW - Oxygen Consumption
KW - RNA, Messenger
KW - Subcellular Fractions
KW - Trans-Activators
KW - Transcription Factors
KW - Up-Regulation
U2 - 10.1213/ANE.0b013e31826c8095
DO - 10.1213/ANE.0b013e31826c8095
M3 - SCORING: Journal article
C2 - 23223114
VL - 116
SP - 83
EP - 92
JO - ANESTH ANALG
JF - ANESTH ANALG
SN - 0003-2999
IS - 1
ER -