Clinical toxicology (Philadelphia, Pa.) · 2025
Exogenous [Pyr1]apelin-13 prevents bupivacaine-induced cardiotoxicity via the apelin (APJ) receptor.
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Chen Chaoxing, Zhao Shishi, Chen Zhengjie, He Yuting, Chen Jiali, Zheng Liangyu, Xia Yun, Papadimos Thomas J, Shi Kejian, Chen Hongfei, Liu Le, Xu Xuzhong, Jin Zhousheng, Wang Quanguang
Аннотация
BACKGROUND: Abnormal energy metabolism is an important mechanism in the development of bupivacaine-induced cardiotoxicity. Apelin, a peptide derived from adipocytes, plays a pivotal role in both energy metabolism and the regulation of the cardiovascular system, thereby potentially linking it to bupivacaine-induced cardiotoxicity.
METHODS: Our study employed both an ex vivo Sprague-Dawley neonatal rat cardiomyocyte-based bupivacaine toxicity model and an in vivo bupivacaine-induced adult male Sprague-Dawley rat asystole model. Beating frequency ratio, survival rate and oxygen consumption rate were assessed, and changes in mitochondrial ultrastructure were examined. The expression of adenosine monophosphate-activated protein kinase, acetyl coenzyme-A carboxylase, and peroxisome proliferator-activated receptor-gamma coactivator-1α were quantified.
RESULTS: Exogenous [Pyr1]apelin-13 22 μmol/L improved bupivacaine-induced 90 μmol/L inhibition of the cardiomyocyte beating frequency ratio (mean difference 0.48; 95% CI: 0.35-0.62; P <0.001; n = 5) after a 20 min exposure. [Pyr1]apelin-13 also preserved mitochondrial ultrastructure, modulated oxygen consumption rate, and these protective effects were nullified by apelin receptor short hairpin ribonucleic acid. Exogenous [Pyr1]apelin-13 0.15 mg/kg improved the survival rate in adult male rats with bupivacaine-induced 30 mg/kg asystole (12/12 [100%] versus 6/12 [50%]; P = 0.014), while the presence of the specific apelin receptor antagonist Phe13-Ala, at an equivalent dose abolished this benefit (3/12 [25%]). Additionally, apelin treatment was associated with upregulation of metabolic proteins, including adenosine monophosphate-activated protein kinase, acetyl coenzyme-A carboxylase, and peroxisome proliferator-activated receptor-gamma coactivator-1α in the heart tissue over a 60 min period.
DISCUSSION: Despite apelin being identified initially as the sole apelin receptor ligand, evidence shows distinct effects between apelin and apelin receptor knockout models, as well as Phe13-Ala and adenovirus-mediated apelin receptor interventions. We confirmed that the cardioprotective effects of apelin depend on apelin receptor interaction.
CONCLUSIONS: Exogenous [Pyr1]apelin-13 reversed bupivacaine-induced cardiotoxicity in adult male Sprague-Dawley rats and neonatal cardiomyocytes via modulation of mitochondrial structure and function, mediated through the apelin receptor.
METHODS: Our study employed both an ex vivo Sprague-Dawley neonatal rat cardiomyocyte-based bupivacaine toxicity model and an in vivo bupivacaine-induced adult male Sprague-Dawley rat asystole model. Beating frequency ratio, survival rate and oxygen consumption rate were assessed, and changes in mitochondrial ultrastructure were examined. The expression of adenosine monophosphate-activated protein kinase, acetyl coenzyme-A carboxylase, and peroxisome proliferator-activated receptor-gamma coactivator-1α were quantified.
RESULTS: Exogenous [Pyr1]apelin-13 22 μmol/L improved bupivacaine-induced 90 μmol/L inhibition of the cardiomyocyte beating frequency ratio (mean difference 0.48; 95% CI: 0.35-0.62; P <0.001; n = 5) after a 20 min exposure. [Pyr1]apelin-13 also preserved mitochondrial ultrastructure, modulated oxygen consumption rate, and these protective effects were nullified by apelin receptor short hairpin ribonucleic acid. Exogenous [Pyr1]apelin-13 0.15 mg/kg improved the survival rate in adult male rats with bupivacaine-induced 30 mg/kg asystole (12/12 [100%] versus 6/12 [50%]; P = 0.014), while the presence of the specific apelin receptor antagonist Phe13-Ala, at an equivalent dose abolished this benefit (3/12 [25%]). Additionally, apelin treatment was associated with upregulation of metabolic proteins, including adenosine monophosphate-activated protein kinase, acetyl coenzyme-A carboxylase, and peroxisome proliferator-activated receptor-gamma coactivator-1α in the heart tissue over a 60 min period.
DISCUSSION: Despite apelin being identified initially as the sole apelin receptor ligand, evidence shows distinct effects between apelin and apelin receptor knockout models, as well as Phe13-Ala and adenovirus-mediated apelin receptor interventions. We confirmed that the cardioprotective effects of apelin depend on apelin receptor interaction.
CONCLUSIONS: Exogenous [Pyr1]apelin-13 reversed bupivacaine-induced cardiotoxicity in adult male Sprague-Dawley rats and neonatal cardiomyocytes via modulation of mitochondrial structure and function, mediated through the apelin receptor.