alpha 1-adrenergic agonists precondition rabbit ischemic myocardium independent of adenosine by direct activation of protein kinase C.
alpha 1-adrenergic agonists precondition rabbit ischemic myocardium independent of adenosine by direct activation of protein kinase C.
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DOI：
10.1161/01.res.75.3.576
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发表时间：
1994-09
影响因子：
20.1
通讯作者：
A. Tsuchida;Yongge Liu;G. S. Liu;Michael V. Cohen;J. M. Downey
中科院分区：
文献类型：
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作者：
A. Tsuchida;Yongge Liu;G. S. Liu;Michael V. Cohen;J. M. Downey
兔子的缺血预处理是通过刺激腺苷 A1 受体启动的，从而激活蛋白激酶 C (PKC)。此外，α1-肾上腺素能激动剂同样可以保护缺血性心肌，但对于腺苷受体在这种保护中所起的作用一直存在困惑。为了表征肾上腺素能受体和腺苷受体之间的相互作用并研究 PKC 在这种保护中的可能作用，我们使用了灌注有氧 Krebs' 缓冲液的离体兔心脏。所有心脏均经历30分钟的局部心肌缺血和2小时的再灌注。通过三苯基四唑染色测定梗塞大小。在长期局部缺血前 10 分钟，用 5 分钟去氧肾上腺素 (PE) 输注对心脏进行药物预处理，导致梗死面积（风险区域的 9.7 +/- 1.3%）明显小于对照心脏（31.0 +/- 2.6%，P < .05）。通过施用α-肾上腺素能阻滞剂苯氧苯扎明可以有效地阻断这种保护。甲氧明（一种 α 1a 选择性激动剂）未能起到保护作用，而 α 1b 选择性拮抗剂氯乙基可乐定则中止了 PE 的保护作用。 PKC 的抑制剂多粘菌素 B 也阻断了 PE 的保护作用，这表明 PKC 在预处理中具有重要作用。与 PE 输注同时给予的腺苷受体阻滞剂 8-(对磺基苯基)茶碱 (SPT) 不会影响保护作用，这意味着 α1-激动剂可以独立于腺苷启动保护作用，推测是通过直接与 PKC 偶联。然而，如果在 30 分钟局部缺血期间进行 SPT，PE 的保护作用可能会被阻断。这一观察结果表明，在长时间缺血期间，腺苷受体的占据对于重新激活 PKC 并介导保护是必要的。然而，尽管存在 SPT，但在 5 分钟前开始并持续整个长时间缺血期间添加第二次 PE 输注恢复了 PE 的保护作用。因此，只要在长时间缺血期间至少激活一种受体（α1-肾上腺素或腺苷A1），就能实现保护。这些数据表明，α1 受体不通过腺苷中间体进行预处理，但α1-肾上腺素能受体和腺苷受体激活肌细胞内的平行通路，从而触发和介导保护。
Ischemic preconditioning in the rabbit is initiated by adenosine A1-receptor stimulation, which activates protein kinase C (PKC). Additionally, alpha 1-adrenergic agonists can similarly protect ischemic myocardium, but there has been confusion about the role adenosine receptors play in this protection. To characterize the interaction between adrenergic and adenosine receptors and to study the possible role of PKC in this protection, we used isolated rabbit hearts perfused with oxygenated Krebs' buffer. All hearts were subjected to 30 minutes of regional myocardial ischemia and 2 hours of reperfusion. Infarct size was determined by triphenyltetrazolium staining. Pharmacologic preconditioning in hearts with a 5-minute phenylephrine (PE) infusion 10 minutes before the prolonged regional ischemia resulted in significantly smaller infarcts (9.7 +/- 1.3% of risk area) than in control hearts (31.0 +/- 2.6%, P < .05). This protection could be effectively blocked by administration of the alpha-adrenergic blocker phenoxybenzamine. Methoxamine, an alpha 1a-selective agonist, failed to protect, whereas the alpha 1b-selective antagonist chloroethylclonidine aborted the protective effect of PE. Polymyxin B, an inhibitor of PKC, also blocked the protective effect of PE, implying that PKC has an important role in preconditioning. The adenosine receptor blocker 8-(p-sulfophenyl)theophylline (SPT) given at the same time as the PE infusion did not affect the protection, implying that an alpha 1-agonist could initiate protection independent of adenosine, presumably by direct coupling to PKC. However, the protective effect of PE could be blocked if SPT were administered during the 30-minute regional ischemia. This observation suggested that adenosine receptor occupancy is necessary during long ischemia to reactivate PKC and mediate the protection. However, the addition of a second PE infusion beginning 5 minutes before and continuing throughout the long ischemic period restored the protective effect of PE despite the presence of SPT. Thus, as long as at least one of the receptors (alpha 1-adrenegic or adenosine A1) is activated during long ischemia, protection will be realized. These data indicate that alpha 1 receptors do not precondition through an adenosine intermediate but that alpha 1-adrenergic and adenosine receptors activate parallel pathways within the myocyte that can trigger and mediate protection.