Activation of a renin-angiotensin system in ischemic cardiac sympathetic nerve endings and its association with norepinephrine release.
Activation of a renin-angiotensin system in ischemic cardiac sympathetic nerve endings and its association with norepinephrine release.
复制标题
DOI：
10.1016/s1567-5769(02)00148-0
复制
发表时间：
2002-12
影响因子：
5.6
通讯作者：
R. Levi;R. Silver;Christina J. Mackins;N. Seyedi;Motohiro Koyama
中科院分区：
文献类型：
--
作者：
R. Levi;R. Silver;Christina J. Mackins;N. Seyedi;Motohiro Koyama
我们已经报道，在缺血心脏中，局部形成的缓激肽（BK）和血管紧张素II（Ang II）激活交感神经末梢（SNE）上的B2-和AT 1-受体，促进去甲肾上腺素（NE）转运蛋白向外的逆转（即，载体介导的NE释放）。虽然BK和Ang II都有助于缺血NE的释放，但Ang II可能发挥更重要的作用。由于BK是由缺血性SNE形成的，我们质疑心脏SNE除了是Ang II的靶点之外是否也有助于局部Ang II的形成。从人右心房手术标本中分离SNE，并在缺血条件下孵育。这些SNE通过载体介导的机制释放大量的内源性NE，地昔帕明对这一过程的抑制作用证明了这一点。此外，两种肾素抑制剂，胃蛋白酶抑制剂-A和BILA 2157 BS，ACE抑制剂依那普利拉和AT 1受体拮抗剂EXP 3174阻止缺血NE释放。Western印迹分析显示，心脏SNE中存在肾素。在缺血期间，肾素丰度增加了三倍以上。因此，肾素存在于心脏SNE中，并在缺血期间被激活，最终导致Ang II形成、AT 1受体的刺激和载体介导的NE释放。我们的研究结果揭示了一种新的自分泌机制，通过这种机制，在SNE在心肌缺血时形成的Ang II通过激活关节前AT 1受体来促进载体介导的NE释放。
We had reported that in the ischemic heart, locally formed bradykinin (BK) and angiotensin II (Ang II) activate B2- and AT1-receptors on sympathetic nerve terminals (SNE), promoting reversal of the norepinephrine (NE) transporter in an outward direction (i.e., carrier-mediated NE release). Although both BK and Ang II contribute to ischemic NE release, Ang II is likely to play a more important role. Since BK is formed by ischemic SNE, we questioned whether cardiac SNE also contribute to local Ang II formation, in addition to being a target of Ang II. SNE were isolated from surgical specimens of human right atrium and incubated in ischemic conditions. These SNE released large amounts of endogenous NE via a carrier-mediated mechanism, as evidenced by the inhibitory effect of desipramine on this process. Moreover, two renin inhibitors, pepstatin-A and BILA 2157 BS, the ACE inhibitor enalaprilat and the AT1-receptor antagonist EXP3174 prevented ischemic NE release. Western blot analysis revealed the presence of renin in cardiac SNE. Renin abundance increased more than three-fold during ischemia. Thus, renin is present in cardiac SNE and is activated during ischemia, eventually culminating in Ang II formation, stimulation of AT1-receptors and carrier-mediated NE release. Our findings uncover a novel autocrine mechanism, by which Ang II, formed at SNE in myocardial ischemia, elicits carrier-mediated NE release by activating prejuntional AT1-receptors.