Exploring the role of neurogenic pathway-linked cholecystokinin release in remote preconditioning-induced cardioprotection

Abstract Purpose: The current study explored the involvement of neurogenic pathway-linked cholecystokinin (CCK) release in RIP-induced cardioprotection in rats. Methods: Male Wistar rats were subjected to four cycles of alternate episodes of ischemia and reperfusion (five min each) to induce RIP. Thereafter, the hearts were subjected to global ischemia and reperfusion ex vivo. The myocardial damage was assessed by quantifying the levels of heartspecific biochemicals i.e. LDH-1, CK-MB and cTnT. Apoptotic cell injury was assessed by measuring the levels of caspase-3 and Bcl-2. The levels of CCK were measured in the plasma following RIP. Results: Exposure to RIP significantly increased the plasma levels of CCK and attenuated IR-induced myocardial injury. Administration of CCK antagonist, proglumide significantly attenuated RIP-induced cardioprotection. Administration of hexamethonium, a ganglion blocker, abolished RIP-induced increase in plasma CCK levels and cardioprotective effects. Exogenous delivery of CCK-8 restored the effects of RIP in hexamethonium treated animals. Conclusion: RIP activates the neurogenic pathway that may increase the plasma levels of CCK, which may act on the heart-localized CCK receptors to produce cardioprotection against I/R injury.

摘要

研究目的：本研究旨在探讨神经通路介导的胆囊收缩素（cholecystokinin, CCK）释放在大鼠缺血后处理（RIP）诱导的心肌保护效应中的作用。

方法：选取雄性Wistar大鼠，通过4轮交替的缺血-再灌注处理（每次持续5分钟）构建缺血后处理模型。随后对离体心脏进行全心缺血再灌注造模。通过定量检测心肌特异性生化标志物——乳酸脱氢酶同工酶1（LDH-1）、肌酸激酶同工酶MB（CK-MB）及心肌肌钙蛋白T（cTnT）的水平评估心肌损伤程度；通过检测半胱氨酸天冬氨酸蛋白酶3（caspase-3）与B细胞淋巴瘤-2蛋白（Bcl-2）的水平评估细胞凋亡性损伤程度；并在缺血后处理后检测血浆中CCK的水平。

结果：缺血后处理可显著升高大鼠血浆CCK水平，并减轻缺血再灌注（I/R）诱导的心肌损伤。给予胆囊收缩素拮抗剂丙谷胺（proglumide）可显著削弱缺血后处理介导的心肌保护效应。给予神经节阻滞剂六甲铵（hexamethonium）可阻断缺血后处理引起的血浆CCK水平升高及其心肌保护作用。向经六甲铵处理的动物外源性给予八肽胆囊收缩素（CCK-8），可恢复缺血后处理的效应。

结论：缺血后处理可激活神经通路，进而升高血浆CCK水平；CCK可通过作用于心脏局部的胆囊收缩素受体，发挥对抗缺血再灌注损伤的心肌保护作用。