Experimental Evidence in Favor of Role of Intracellular Actions of Bupivacaine in Myocardial Depression

Je, de La Coussaye; Bassoul, B.; Albat, B; Pa, Peray; Jp, Gagnol; Jj, Eledjam; Sassine, A

doi:10.1213/00000539-199205000-00014

Cited by 16 publications

(11 citation statements)

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“…Eledjam et al (1989) suggested that the inhibition of energy metabolism and proton transfer could be closely relevant to bupivacaine-induced cardiotoxicity. This was also supported by de La Coussaye et al (1992). In 1998, Sztark et al found that bupivacaine directly inhibited complex I of the mitochondrial respiratory chain, thereby impairing mitochondrial respiratory function and energy generation.…”

Section: Introductionmentioning

confidence: 84%

The protective effect of lipid emulsion in preventing bupivacaine-induced mitochondrial injury and apoptosis of H9C2 cardiomyocytes

et al. 2017

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Lipid emulsion (LE) has been shown to be effective in the resuscitation of bupivacaine-induced cardiac arrest, but the precise mechanism of this action has not been fully elucidated. Pursuant to this lack of information on the mechanism in which LE protects the myocardium during bupivacaine-induced toxicity, we explored mitochondrial function and cell apoptosis. H9C2 cardiomyocytes were used in study. Cells were randomly divided in different groups and were cultivated 6 h, 12 h, and 24 h. The mitochondria were extracted and mitochondrial ATP content was measured, as was mitochondrial membrane potential, the concentration of calcium ion (Ca2+), and the activity of Ca2+-ATP enzyme (Ca2+-ATPase). Cells from groups Bup1000, LE group, and Bup1000LE were collected to determine cell viability, cell apoptosis, and electron microscopy scanning of mitochondrial ultrastructure (after 24 h). We found that LE can reverse the inhibition of the mitochondrial function induced by bupivacaine, regulate the concentration of calcium ion in mitochondria, resulting in the protection of myocardial cells from toxicity induced by bupivacaine.

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Section: Introductionmentioning

confidence: 84%

The protective effect of lipid emulsion in preventing bupivacaine-induced mitochondrial injury and apoptosis of H9C2 cardiomyocytes

et al. 2017

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“…This is due both to the intrinsic interest of clarifying the mechanisms of uncoupling by hydrophobic amines, which are largely used as anesthetics, and to an effort to understand the basis of bupivacaine toxicity (49,50), which is exploited to induce cell death in studies of muscle regeneration (1,2). Despite initial controversies, it now appears established that bupivacaine is a bona fide protonophore (8), although it can also form ion pairs with lipophilic anions (11,48).…”

Section: Multiple Effects Of Bupivacaine On Mitochondrial Energymentioning

confidence: 99%

“…Addendum-An additional mechanism that may cause mitochondrial bupivacaine toxicity is inhibition of carnitine transport, which has been demonstrated for heart mitochondria, with an IC 50 …”

Section: Multiple Effects Of Bupivacaine On Mitochondrial Energymentioning

confidence: 99%

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Irwin

Fontaine

Agnolucci

et al. 2002

Journal of Biological Chemistry

163

114

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We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mM or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca 2؉ , release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca 2؉ dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role.

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“…Indeed, experimental and clinical data have demonstrated that these two agents may be less toxic than bupivacaine. 6,7 Although the effects of LAA on myocardial contractility and cardiac conduction, as well as their mechanisms of action have been extensively documented, 6,[8][9][10] there are limited data reporting the effects of LAA on myocardial relaxation processes and diastolic function.…”

mentioning

confidence: 99%

Effects of bupivacaine, levobupivacaine and ropivacaine on myocardial relaxation

David

Ferreti

Amour

et al. 2007

Can J Anesth/J Can Anesth

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CAN J ANESTH 54: 3 www.cja-jca.org March, 2007 Purpose: Ropivacaine and levobupivacaine were developed to reduce the risk of occasional toxicity reported with bupivacaine. While the effects of long-acting local anesthetics (LAAs) on myocardial contractility (inotropy) are well described, their effects on relaxation (lusitropy) remain largely unknown. The present study aimed to compare the effects of LAAs on rat myocardium. Methods:Left ventricular papillary muscles of male Wistar rats were used to compare the inotropic and lusitropic responses of increasing concentrations of LAAs (10 -8 to 10 -3 M) under isometric and isotonic conditions. Data are mean % (SD) of baseline value.Results: Long-acting local anesthetics induced a significant impairment of relaxation in isotonic and isometric conditions. As compared to ropivacaine, bupivacaine and levobupivacaine induced greater negative lusitropic effects in isotony [at 10 -3 M, maximum unloaded shortening velocity ( max Vr) = 27 ± 11 vs 13 ± 6 and 8 ± 5%] and isometry (at 10 -3 M, time-to-halfrelaxation: 106 ± 10 vs 127 ± 17 and 133 ± 17%). When the comparison was made with equipotent concentrations, the negative lusitropic effects induced with levobupivacaine were significantly greater than those of bupivacaine and ropivacaine in isometric and isotonic conditions (at 10 -3 M, max Vr = 7 ± 4 vs 13 ± 6 and 17 ± 4 %). As previously described, LAAs also induced concentration-dependent negative inotropic effects that were greater for levobupivacaine compared to equivalent or equipotent concentrations of bupivacaine and ropivacaine.Conclusions: Long-acting local anesthetics induce marked negative inotropic and lusitropic effects. Among LAAs, levobupivacaine exerts the greater depressant effects. Impairment of calcium handling and sarcoplasmic reticulum could explain the differential responses to local anesthetics. Objectif : La ropivacaïne et la lévobupivacaïne ont été dévelop-pées pour réduire le risque d'accidents sévères observés avec la bupivacaïne. Si les effets des anesthésiques locaux (LAAs) sur la contractilité myocardique (inotropie) sont bien décrits, les effets sur la relaxation (lusitropie) restent peu explorés. Cette étude a eu pour objectif de comparer les effets des LAAs chez le rat. Méthode : Les effets de concentrations croissantes de LAAs (10 -8 à 10 -3 M) sur les réponses inotropes et lusitropes ont été comparés à l'aide d'un modèle de muscles papillaires. Les valeurs sont exprimées en % de la valeur de base (moyenne ± ET). Résultats

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Experimental Evidence in Favor of Role of Intracellular Actions of Bupivacaine in Myocardial Depression

Cited by 16 publications

References 0 publications

The protective effect of lipid emulsion in preventing bupivacaine-induced mitochondrial injury and apoptosis of H9C2 cardiomyocytes

The protective effect of lipid emulsion in preventing bupivacaine-induced mitochondrial injury and apoptosis of H9C2 cardiomyocytes

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Effects of bupivacaine, levobupivacaine and ropivacaine on myocardial relaxation

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