A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels.
A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels.
复制标题
腺苷诱导的狗心脏保护作用和缺血预处理的比较。
作者：
Z. Yao;G. Gross
背景
腺苷被认为是缺血预处理的重要介质。最近显示，冠状动脉内施用腺苷可以模拟离体兔心脏预处理的效果。然而，尚不清楚该试剂是否可以在体内或其他物种中复制预处理的效果。因此，本研究的第一个目标是确定腺苷是否可以将心肌坏死限制到与麻醉狗预处理相同的程度。第二个目标是确定腺苷诱导的心脏保护作用的持续时间是否与缺血预处理的持续时间一样长。最后，第三个目标是确定腺苷是否通过 KATP 通道介导其心脏保护作用，该通道已被证明是包括狗在内的多种动物物种的预处理的重要介质。
方法和结果
对巴比妥麻醉的开胸狗进行 60 分钟的左冠状动脉前降支 (LAD) 闭塞，然后进行 4 小时的再灌注。预处理是通过 10 分钟的 LAD 闭塞，然后在 60 分钟的闭塞期之前进行 10 或 60 分钟的再灌注来引发的。将腺苷（400 微克/分钟）或等体积的盐水注入 LAD 10 分钟，然后在 60 分钟缺血性损伤之前进行 10 或 60 分钟的无药期。格列本脲（0.3 mg/kg，静脉注射）是一种选择性 KATP 通道阻滞剂，在腺苷给药前 15 分钟给予，另一种选择性 KATP 通道阻滞剂 5-羟基癸酸（5-HD，3 mg/min IC）与腺苷同时注入 LAD 10 分钟。在闭塞 5 分钟时测量透壁心肌血流量，并通过三苯基四唑染色确定梗塞面积并表示为危险面积 (AAR) 的百分比。各组之间的血流动力学、侧支血流或 AAR 没有显着差异。再灌注 10 分钟或 60 分钟的预处理使梗塞面积显着减小 (P < .05)（分别为 6.7 +/- 2.5% 和 8.7 +/- 2.6%，而对照组为 26.9 +/- 4.3%）。在闭塞 60 分钟之前给予腺苷 10 分钟的无药期，导致梗死面积显着减小，与预处理相似（对照组为 9.6 +/- 1.7%，对照组为 26.9 +/- 4.3%）；然而，当腺苷给药后允许 60 分钟的禁药期时，保护作用消失（对照组为 23.0 +/- 2.4%，对照组为 26.9 +/- 4.3%）。此外，格列本脲或 5-HD 治疗完全消除了腺苷的保护作用（分别为 26.4 +/- 6.8 和 25.0 +/- 4.4%，而对照组为 26.9 +/- 4.3%）。
结论
这些结果清楚地表明：（1）10分钟的腺苷冠状动脉内输注在减少狗的心肌坏死方面表现出与缺血预适应相同的功效； (2)与预处理类似，腺苷通过心脏KATP通道相关机制介导其心脏保护作用； (3) 腺苷诱导的心脏保护作用是短暂的（60 分钟内消失），而缺血预处理可持续至少 60 分钟。这些数据支持这样的假设：缺血期间释放的内源性腺苷是缺血预处理的重要介质；然而，外源性腺苷和预处理的作用时间进程之间存在重要差异，这表明还可能涉及其他因素。
BACKGROUND
Adenosine has been proposed to be an important mediator of ischemic preconditioning. Intracoronary administration of adenosine has recently been shown to mimic the effects of preconditioning in isolated rabbit hearts. However, it is not known whether this agent can duplicate the effects of preconditioning in vivo or in other species. Thus, the first objective of the present study was to determine whether adenosine can limit myocardial necrosis to the same extent as preconditioning in anesthetized dogs. A second objective was to determine whether the duration of the adenosine-induced cardioprotection persisted as long as that of ischemic preconditioning. Finally, a third aim was to determine whether adenosine mediates its cardioprotection via the KATP channel, which has been shown to be an important mediator of preconditioning in several animal species, including dogs.
METHODS AND RESULTS
Barbital-anesthetized open-chest dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion followed by 4 hours of reperfusion. Preconditioning was elicited by 10 minutes of LAD occlusion followed by 10 or 60 minutes of reperfusion before the 60-minute occlusion period. Adenosine (400 micrograms/min) or an equivalent volume of saline was infused into the LAD for 10 minutes, followed by a 10- or 60-minute drug-free period before the 60-minute ischemic insult. Glibenclamide (0.3 mg/kg i.v.), a selective KATP channel blocker, was given 15 minutes before adenosine administration, and another selective KATP channel blocker, 5-hydroxydecanoate (5-HD, 3 mg/min IC) was infused concomitantly with adenosine into the LAD for 10 minutes. Transmural myocardial blood flow was measured at 5 minutes of occlusion, and infarct size was determined by triphenyltetrazolium staining and expressed as a percent of the area at risk (AAR). There were no significant differences in hemodynamics, collateral blood flow, or AAR between groups. Preconditioning with either 10 or 60 minutes of reperfusion produced a marked reduction (P < .05) in infarct size (6.7 +/- 2.5% and 8.7 +/- 2.6%, respectively, versus 26.9 +/- 4.3% in controls). Administration of adenosine with a 10-minute drug-free period before 60 minutes of occlusion resulted in a marked decrease in infarct size similar to that seen with preconditioning (9.6 +/- 1.7% versus 26.9 +/- 4.3% in controls); however, the protection disappeared when a 60-minute drug-free period was allowed after adenosine administration (23.0 +/- 2.4% versus 26.9 +/- 4.3% in controls). In addition, treatment with either glibenclamide or 5-HD completely abolished the protective effects of adenosine (26.4 +/- 6.8 and 25.0 +/- 4.4%, respectively, versus 26.9 +/- 4.3% in controls).
CONCLUSIONS
These results clearly reveal that (1) a 10-minute intracoronary infusion of adenosine exhibits the same efficacy as ischemic preconditioning in reducing myocardial necrosis in dogs; (2) similar to preconditioning, adenosine mediates its cardioprotection via a cardiac KATP channel-linked mechanism; and (3) adenosine-induced cardioprotection is transient (disappearing within 60 minutes), whereas ischemic preconditioning persists for at least 60 minutes. These data support the hypothesis that endogenous adenosine released during ischemia is an important mediator of ischemic preconditioning; however, important differences exist between the time course of effects of exogenously administered adenosine and preconditioning, which suggests that other factors may also be involved.
百日咳毒素预处理可阻断预处理的保护作用：G 蛋白机制的证据。
影响因子：
5
作者：
Thornton,JD;Liu,GS;Downey,JM
通讯作者：
Downey,JM
影响因子：
--
作者：
KIRSCH, GE;CODINA, J;BROWN, AM
通讯作者：
BROWN, AM
影响因子：
20.1
作者：
MURRY, CE;RICHARD, VJ;JENNINGS, RB
通讯作者：
JENNINGS, RB