<i>In Vitro</i>Negative Inotropic Effect of Low Concentrations of Bupivacaine Relates to Diminished Ca2+ Sensitivity but Not to Ca2+ Handling or β-Adrenoceptor Signaling

Flenner, Frederik; Arlt, Nicole; Nasib, Mahtab; Schobesberger, Sophie; Koch, Thea; Ravens, Ursula; Friedrich, Felix W.; Nikolaev, Viacheslav O.; Christ, Torsten; Stehr, Sebastian

doi:10.1097/aln.0000000000002180

Cited by 3 publications

(3 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In mammalian ventricular muscle, bupivacaine was noted to lower myofilament calcium sensitivity more effectively than ropivacaine ( i.e ., more intracellular calcium required to generate equal force). 47,48 We observed, similar to other studies, that bupivacaine can inhibit sarcoplasmic calcium release (lower peak calcium wave amplitude). The combination of lower myofilament calcium sensitivity and reduced calcium cycling suggests that supplemental calcium might be beneficial in mitigating bupivacaine-induced contractile depression.…”

Section: Discussionsupporting

confidence: 90%

Local Anesthetic Cardiac Toxicity Is Mediated by Cardiomyocyte Calcium Dynamics

et al. 2022

View full text Add to dashboard Cite

Background Long-lasting local anesthetic use for perioperative pain control is limited by possible cardiotoxicity (e.g., arrhythmias and contractile depression), potentially leading to cardiac arrest. Off-target cardiac sodium channel blockade is considered the canonical mechanism behind cardiotoxicity, however, it does not fully explain the observed toxicity variability between anesthetics. We hypothesize that more cardiotoxic anesthetics (e.g., bupivacaine) differentially perturb other important cardiomyocyte functions (e.g., calcium dynamics), which may be exploited to mitigate drug toxicity. Methods We investigated the effects of clinically-relevant concentrations of racemic bupivacaine, levobupivacaine, or ropivacaine on human stem cell-derived cardiomyocyte tissue function. Contractility, rhythm, electromechanical coupling, field potential profile, and intracellular calcium dynamics were quantified using multielectrode arrays and optical imaging. Calcium flux differences between bupivacaine and ropivacaine were probed with pharmacologic calcium supplementation or blockade. In vitro findings were correlated in vivo using an anesthetic cardiotoxicity rat model (females; n=5 per group). Results Bupivacaine more severely dysregulated calcium dynamics than ropivacaine in vitro (e.g., contraction calcium amplitude to 52±11% and calcium-mediated repolarization duration to 122±7% of ropivacaine effects, model estimate ± standard error). Calcium supplementation improved tissue contractility and restored normal beating rhythm (to 101±6%, and 101±26% of control, respectively) for bupivacaine-treated tissues, but not ropivacaine (e.g., contractility at 80±6% of control). Similarly, calcium pre-treatment mitigated anesthetic-induced arrhythmias and cardiac depression in rats, improving animal survival for bupivacaine by 8.3±2.4 min, but exacerbating ropivacaine adverse effects (reduced survival by 13.8±3.4 min and time to first arrhythmia by 12.0±2.9 min). Calcium channel blocker nifedipine co-administration with bupivacaine, but not ropivacaine, exacerbated cardiotoxicity, supporting the role of calcium flux in differentiating toxicity. Conclusions Our data illustrate differences in calcium dynamics between anesthetics, and how calcium may mitigate bupivacaine cardiotoxicity. Moreover, our findings suggest that bupivacaine cardiotoxicity risk may be higher than for ropivacaine in a calcium deficiency context.

show abstract

Section: Discussionsupporting

confidence: 90%

Local Anesthetic Cardiac Toxicity Is Mediated by Cardiomyocyte Calcium Dynamics

et al. 2022

View full text Add to dashboard Cite

show abstract

“…However, overdose or accidental intravasal application of bupivacaine can result in significant adverse effects. For every 1000 peripheral nerve blocks, 0.04 to 1.8 cases of myocardial toxicity are likely to occur, leading to severe symptoms [ 6 ]. Bupivacaine reportedly induces muscle toxicity in skeletal muscles [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function

et al. 2020

View full text Add to dashboard Cite

Background: Electroacupuncture is well known for its advantageous neuroanalgesic and therapeutic effects on myocardial ischemia-reperfusion injury. The purpose of the present research was to verify whether electroacupuncture can alleviate bupivacaine-induced myocardial injury. Methods: Specific pathogen-free Wistar rats were used to establish the bupivacaine-induced myocardial injury model. Western blot, PCR, transmission electron microscope and enzyme-linked immunosorbent (ELISA) methods were used to evaluate bupivacaine-induced structure injury and dysfunction of the mitochondria as well as the alleviating effects of lipid emulsion, acupoint injection, and electroacupuncture pre-treatment of the oxidase stress response. Results: Bupivacaine caused structural damage, degradation, and swelling of mitochondria. Furthermore, it reduced adenosine triphosphate (ATP) synthesis and impaired energy metabolism in the mitochondria. Structural and functional impairment of the mitochondria was alleviated via lipid emulsion injection, acupoint injection, and electroacupuncture pre-treatment. Electroacupuncture pre-treatment of PC6 yielded a greater alleviating effect than others approaches. Following electroacupuncture pre-treatment of PC6 point, the number of mitochondria increased; apoptosis was reduced, enzymatic activity of cytochrome C oxidase (COX) and superoxide dismutase and expression of uncoupling protein 2, voltage-dependent anion channel 1, and Bcl 2 were upregulated and SLC25A6, MDA levels were downregulated. Additionally, our findings indicated that electroacupuncture pre-treatment of PC6 point exerted an effect on the mitochondria via the mitochondrial-transcription-factor-A/nuclear-respiratory-factor-1/proliferatoractivated-receptor-gamma-coactivator-1 pathway. Conclusion: The present study revealed that electroacupuncture pre-treatment of PC6 could effectively alleviate bupivacaine-induced myocardial mitochondrial damage, thereby providing a theoretical basis for clinical studies and applications of this treatment method.

show abstract

“…However, overdose or accidental intravasal application of bupivacaine can result in signi cant adverse effects. For every 1,000 peripheral nerve blocks, 0.04 to 1.8 cases of myocardial toxicity are likely to occur, leading to severe symptoms [6].…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function

Wang

Liang

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Electroacupuncture is well known for its advantageous neuroanalgesic and therapeutic effects on myocardial ischemia-reperfusion injury. The purpose of the present research was to verify whether electroacupuncture can alleviate bupivacaine-induced myocardial injury. Methods Specific-pathogen-free Wistar rats were used to establish the bupivacaine-induced myocardial injury model. Western blot, PCR, transmission electron microscope and enzyme-linked immunosorbent (ELISA) methods were used to evaluate bupivacaine-induced structure injury and dysfunction of the mitochondria as well as the alleviating effects of lipid emulsion, acupoint injection, and electroacupuncture pre-treatment of the oxidase stress response. Results Bupivacaine caused structural damage, degradation, and swelling of mitochondria. Furthermore, it reduced adenosine triphosphate (ATP) synthesis and impaired energy metabolism in the mitochondria. Structural and functional impairment of the mitochondria was alleviated via lipid emulsion injection, acupoint injection, and electroacupuncture pre-treatment. Electroacupuncture pre-treatment of PC6 yielded a greater alleviating effect than others approaches. Following electroacupuncture pre-treatment of PC6 point, the number of mitochondria increased; apoptosis was reduced, enzymatic activity of cytochrome C oxidase (COX) and superoxide dismutase and expression of uncoupling protein 2, voltage-dependent anion channel 1, and Bcl 2 were upregulated and SLC25A6, MDA levels were downregulated. Additionally, our findings indicated that electroacupuncture pre-treatment of PC6 point exerted an effect on the mitochondria via the mitochondrial-transcription-factor-A / nuclear-respiratory-factor-1 / proliferator-activated-receptor-gamma-coactivator -1 pathway. Conclusion The present study revealed that electroacupuncture pre-treatment of PC6 could effectively alleviate bupivacaine-induced myocardial mitochondrial damage, thereby providing a theoretical basis for clinical studies and applications of this treatment method.

show abstract

In VitroNegative Inotropic Effect of Low Concentrations of Bupivacaine Relates to Diminished Ca2+ Sensitivity but Not to Ca2+ Handling or β-Adrenoceptor Signaling

Cited by 3 publications

References 45 publications

Local Anesthetic Cardiac Toxicity Is Mediated by Cardiomyocyte Calcium Dynamics

Local Anesthetic Cardiac Toxicity Is Mediated by Cardiomyocyte Calcium Dynamics

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function

Contact Info

Product

Resources

About