Exogenous [Pyr 1 ]apelin-13 prevents bupivacaine-induced cardiotoxicity via the receptor APJ

Abstract

Abstract Backgrounds Abnormal energy metabolism is an important mechanism in bupivacaine-induced cardiotoxicity. Apelin, an adipocyte-derived peptide involved in energy metabolism and regulation of the cardiovascular system, may be linked to bupivacaine-induced cardiotoxicity. Here we investigated the role of apelin in bupivacaine-induced cardiotoxicity and its relationship with energy metabolism. Methods We used both an ex vivo Sprague-Dawley (SD) neonatal rat cardiomyocyte toxicity model and an in vivo bupivacaine-induced rat asystole model to investigate the effect and mechanism of exogenous [Pyr1]apelin-13 in bupivacaine-induced cardiotoxicity. Results Exogenous [Pyr1]apelin-13 (22 μM) prevented bupivacaine-induced (90 μM) inhibition of the cardiomyocyte beating frequency (mean difference: 0.48, 95% CI: 0.35 to 0.62 versus C-bupi, p<0.001, n=5) in cells treated with bupivacaine for 60 minutes, preserved the mitochondrial ultrastructure and regulated the oxygen consumption rate , and these effects were inhibited by APJ shRNA. Exogenous [Pyr1]apelin-13 (150 μg·kg-1) increased the survival rate of SD rats with bupivacaine-induced (30 mg·kg-1) asystole (12/12 (100%) versus 6/12 (50%), p=0.014), while F13A (150 μg·kg-1), an APJ antagonist, abolished this response (3/12 (25%)). Apelin also increased the expression of adenosine monophosphate-activated protein kinase, acetyl Co-A carboxylase, and peroxisome proliferator-activated receptor-gamma coactivator-1α in SD rats heart tissue. Conclusion Exogenous [Pyr1]apelin-13 prevented bupivacaine-induced cardiotoxicity via the receptor APJ in adult male SD rats and SD neonatal rat cardiomyocytes through the preservation of mitochondrial structure and function.