腺苷和乙酰胆碱后适应诱导的心肌保护作用

近年来缺血后适应的提出成为抗再灌注损伤的里程碑,其良好的临床可控性和可靠的保护效应引起人们广泛关注。缺血后适应即在心肌长时间缺血后再灌注之前,进行数次短暂的再灌注,缺血的循环处理,诱导产生心肌保护效应,其循环次数和间隔时间存在种属差异。研究证实后适应不仅限制急性期梗死面积,还可以减轻长期损伤,其是否与保护血管内皮、抑制中性粒细胞介导的氧化损伤相关还存在争议。上调再灌注损伤补救激酶（reperfusion injury salvageHnase,RISK）通路是后适应保护的重要机制之一,即激活磷脂酰肌醇一3激酶（phosphatidy linositol3-kinase,P13K）-Akt途径和,或细胞外信号调节激酶（extracellular signal-regulatedkinase,ERK）途径,抑制线粒体通透性转换孔的开放,减少细胞凋亡和坏死。但是这两条途径的地位和关系还有待于进一步研究。为了更加适用于临床,研究者将机械调控转变为药物干预,观察药物能否模拟缺血后适应发挥保护作用,即药物后适应。腺苷是研究最广泛,也是最有希望成为临床正式用药的一种药物。我们实验室首先提出了乙酰胆碱可以模拟缺血后适应,通过线粒体ATP敏感钾通道发挥心肌保护效应。本文着重阐述缺血后适应保护缺血,再灌注损伤的效应和信号转导通路,尤其是腺苷和乙酰胆碱模拟药物后适应的可能机制和临床应用。     

Cardioprotection by ischemic postconditioning is lost in isolated perfused heart from diabetic rats: Involvement of transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P

We previously found that the expression of transient receptor potential vanilloid 1 (TRPV1) and contents of calcitonin gene-related peptide (CGRP) and substance P (SP), two main neuropeptides released from TRPV1, were decreased in diabetic hearts. This study aimed to test whether decreased TRPV1, CGRP and SP levels were responsible for the loss of cardioprotection by ischemic postconditioning (IPostC) in isolated perfused heart from streptozotocin-induced diabetic rats. IPostC effectively protected non-diabetic hearts against ischemia/reperfusion injury by improving cardiac function and lowering creatine kinase (CK) and cardiac troponin I (cTnI) release, which could be abolished by inhibiting TRPV1, CGRP receptor or SP receptor. However, IPostC had no effect on cardiac function and the release of CK and cTnI in diabetic hearts regardless of whether TRPV1, CGRP receptor or SP receptor were inhibited. CGRP or SP-induced postconditioning significantly prevented both non-diabetic and diabetic hearts from ischemia/reperfusion injury by improving cardiac function and lowering CK and cTnI release. Additionally, IPostC markedly increased CGRP and SP release in non-diabetic hearts, which could be reversed with TRPV1 inhibition, but not CGRP receptor or SP receptor inhibition. However, IPostC failed to affect CGRP and SP release in diabetic hearts in the presence or absence of TRPV1, CGRP receptor or SP receptor inhibition. These results indicate that the loss of cardioprotection by IPostC during diabetes is partly associated with a failure to increase CGRP and SP release, likely due to decreased TRPV1 expression and CGRP and SP contents in diabetic hearts.     

心肌缺血后处理胞内信号转导研究进展

缺血后处理对心肌再灌注损伤的保护是多因素参与的复杂过程。后处理对心肌的保护除了通过减少活性氧类物质的产生、抑制线粒体内钙超载、减轻内皮功能失调等被动作用外,还可主动激活再灌注损伤补救激酶（reperfusion injury salvage kinase,RISK）途径及其他蛋白激酶而实现。本文将对心肌缺血后处理中RISK通路的研究进展作一综述。