Dataset Information

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study.

ABSTRACT:

Introduction

Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats.

Methods

A rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg^-1.min^-1, and serial doses of apelin-13 (50, 150 and 450 μg.kg^-1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay.

Results

Compared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05).

Conclusion

Exogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.

SUBMITTER: Cai X

PROVIDER: S-EPMC11015498 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study.

Cai Xixi X Liu Le L Xia Fangfang F Papadimos Thomas J TJ Wang Quanguang Q

Brazilian journal of anesthesiology (Elsevier) 20240405 3

<h4>Introduction</h4>Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats.<h4>Methods</h4>A rat model of cardiac suppression was established by a 3-min continuous intravenous in ...[more]

PMID: 38583586

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Project description:IntroductionIntravenous lipid emulsions (ILE) have been credited for successful resuscitation in drug intoxication cases where other cardiac life-support methods have failed. However, inter-individual variability can function as a confounder that challenges our ability to define the scope of efficacy for lipid interventions, particularly as relevant data are scarce. To address this challenge, we developed a quantitative systems pharmacology model to predict outcome variability and shed light on causal mechanisms in a virtual population of rats subjected to bupivacaine toxicity and ILE intervention.Materials and methodsWe combined a physiologically based pharmacokinetic-pharmacodynamic model with data from a small study in Sprague-Dawley rats to characterize individual-specific cardiac responses to lipid infusion. We used the resulting individual parameter estimates to posit a population distribution of responses to lipid infusion. On that basis, we constructed a large virtual population of rats (N = 10,000) undergoing lipid therapy following bupivacaine cardiotoxicity.ResultsUsing unsupervised clustering to assign resuscitation endpoints, our simulations predicted that treatment with a 30% lipid emulsion increases bupivacaine median lethal dose (LD50) by 46% when compared with a simulated control fluid. Prior experimental findings indicated an LD50 increase of 48%. Causal analysis of the population data suggested that muscle accumulation rather than liver accumulation of bupivacaine drives survival outcomes.ConclusionOur results represent a successful prediction of complex, dynamic physiological outcomes over a virtual population. Despite being informed by very limited data, our mechanistic model predicted a plausible range of treatment outcomes that accurately predicts changes in LD50 when extrapolated to putatively toxic doses of bupivacaine. Furthermore, causal analysis of the predicted survival outcomes indicated a critical synergy between scavenging and direct cardiotonic mechanisms of ILE action.

Dataset Information

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study.

Introduction

Methods

Results

Conclusion

Publications

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study.

Similar Datasets

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