Myocardial accumulation of bupivacaine and ropivacaine is associated with reversible effects on mitochondria and reduced myocardial function

TY - JOUR

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 -