Exogenous [Pyr1]apelin-13 prevents bupivacaine-induced cardiotoxicity via the apelin (APJ) receptor

Clin Toxicol (Phila). 2025 Jun 4:1-11. doi: 10.1080/15563650.2025.2510528. Online ahead of print.

ABSTRACT

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.

PMID:40464056 | DOI:10.1080/15563650.2025.2510528