Ischemic preconditioning and the β-adrenergic signal transduction pathway
Ischemic preconditioning and the β-adrenergic signal transduction pathway
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DOI：
10.1161/01.cir.100.9.958
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发表时间：
1999-08-31
期刊：
影响因子：
37.8
通讯作者：
Moolman, JA
中科院分区：
文献类型：
--
作者：
Lochner, A;Genade, S;Moolman, JA
背景-我们实验室以前的研究表明，在多周期预处理（PC）方案中，组织cAMP周期性增加，随后在持续缺血期间cAMP积累减弱。本研究的目的是确定是否缺血诱导激活的β-肾上腺素能信号通路可以作为触发器在引发protection.Methods和Results-isolated灌注大鼠心脏预处理3X 5分钟的全球缺血，穿插5分钟的再灌注。通过在PC方案结束时给予β-肾上腺素能激动剂后测量组织cAMP生成来评估β-肾上腺素能反应性，在不同时间评估组织cAMP、腺苷酸环化酶和蛋白激酶A（PKA）活性和β-肾上腺素能受体特征。通过研究全脑缺血25分钟后再灌注期间的功能恢复，研究了cAMP生成在引发PC中的作用。（1）触发期cAMP的增加被β-肾上腺素能受体阻滞剂阿普洛尔7.5 × 10（-5）mol/L阻止，（2）cAMP的增加被给予毛喉素10（-7）和10（-6）mol/L或异丙肾上腺素10（-8）、10（-7）和10（-6）mol/L。间歇性缺血导致实验结束时β-肾上腺素能反应性降低，尽管β-肾上腺素能受体群的B-max和K-d值以及腺苷酸环化酶和PKA活性增加。在持续性缺血前消除cAMP的周期性增加减弱了心肌对缺血的保护作用，而激动剂引起保护作用。保护和β-肾上腺素能脱敏之间没有明确的相关性observed. Conclusions-缺血诱导的激活的β-肾上腺素能信号通路在预处理过程中也应该被认为是一个触发器，在引发预处理。
Background-Previous studies from our laboratory showed cyclic increases in tissue cAMP during a multiple-cycle preconditioning (PC) protocol, followed by attenuated cAMP accumulation during sustained ischemia. The aim of this study was to determine whether ischemia-induced activation of the beta-adrenergic signaling pathway could act as a trigger in eliciting protection.Methods and Results-Isolated perfused rat hearts were preconditioned by 3X5 minutes of global ischemia, interspersed by 5 minutes of reperfusion. beta-Adrenergic responsivity was assessed by measurement of tissue cAMP generation after beta-adrenergic agonist administration at the end of the PC protocol, Tissue cAMP, adenylyl cyclase, and protein kinase A (PKA) activities and beta-adrenergic receptor characteristics were assessed at different times. The role of cAMP generation in eliciting PC was studied by investigation of functional recovery during reperfusion after 25 minutes of global ischemia after(1) cAMP increases in the trigger period were prevented with the beta-adrenergic blocker alprenolol 7.5x10(-5) mol/L and (2) increases in cAMP were elicited by administration of forskolin 10(-7) and 10(-6) mol/L or isoproterenol 10(-8), 10(-7), and 10(-6) mol/L. Intermittent ischemia resulted in reduced beta-adrenergic responsivity at the end of the protocol, although B-max and K-d values of the beta-adrenergic receptor population and adenylyl cyclase and PKA activities were increased, Abolishment of cyclic increases in cAMP before sustained ischemia attenuated myocardial protection against ischemia, whereas agonists elicited protection. No clear correlation between protection and beta-adrenergic desensitization was observed.Conclusions-Ischemia-induced activation of the beta-adrenergic signaling pathway during preconditioning should also be considered a trigger in eliciting preconditioning.