Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study
A apelina-13 reverte a cardiotoxicidade induzida pela bupivacaína: um estudo experimental
Xixi Cai, Le Liu, Fangfang Xia, Thomas J. Papadimos, Quanguang Wang
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.
Keywords
Resumo
Introdução
A parada cardíaca ou arritmia causada pela bupivacaína pode ser refratária ao tratamento. Foi relatado que a apelina aumenta diretamente a frequência da ativação espontânea e a propagação de potenciais de ação, promovendo, em última análise, a contratilidade cardíaca. Este estudo teve como objetivo investigar os efeitos da apelina-13 na reversão da supressão cardíaca induzida pela bupivacaína em ratos.
Métodos
Um modelo de supressão cardíaca em ratos foi estabelecido por infusão intravenosa contínua de bupivacaína durante 3 minutos na taxa de 5 mg.kg-1.min-1 e doses seriadas de apelina-13 (50, 150 e 450 μg.kg-1) foram administrados para resgatar a supressão cardíaca para identificar sua relação dose-resposta. Usamos F13A, um inibidor do receptor semelhante à angiotensina 1 (APJ), e o inibidor da proteína quinase C (PKC) queleritrina para reverter os efeitos da apelina-13. Além disso, as expressões proteicas de PKC, Nav1.5 e APJ em tecidos ventriculares foram medidas utilizando western blotting e ensaio de imunofluorescência.
Resultados
Em comparação com os ratos controle, os ratos submetidos à administração intravenosa contínua de bupivacaína apresentaram estabilidade hemodinâmica prejudicada. A administração de apelina-13, de maneira dose-dependente, melhorou significativamente os parâmetros hemodinâmicos em ratos com supressão cardíaca induzida por bupivacaína (p <0,05), e o tratamento com apelina-13 também regulou significativamente as expressões proteicas de p-PKC e Nav1.5 (p < 0,05), esses efeitos foram anulados por F13A ou queleritrina (p < 0,05).
Conclusão
A apelina-13 exógena, pelo menos em parte, ativa a via de sinalização PKC através do sistema apelina/APJ para melhorar a função cardíaca em um modelo de supressão cardíaca induzida por bupivacaína em ratos.
Palavras-chave
References
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Submitted date:
09/04/2023
Accepted date:
03/26/2024
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