Pathways for angiotensin II generation in intact human tissue - Evidence from comparative pharmacological interruption of the renin system
Pathways for angiotensin II generation in intact human tissue - Evidence from comparative pharmacological interruption of the renin system
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DOI：
10.1161/01.hyp.32.3.387
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发表时间：
1998-09-01
期刊：
影响因子：
8.3
通讯作者：
Price, DA
中科院分区：
文献类型：
--
作者：
Hollenberg, NK;Fisher, NDL;Price, DA
多种证据表明，心脏、大动脉和肾脏中存在血管紧张素转换酶 (ACE) 生成血管紧张素 II (Ang II) 的替代途径。对心脏和大动脉的完整组织、匀浆或膜分离物进行的体外研究已反复证明了此类途径，但问题仍未解决，因为所使用的方法无法从体外推断到体内情况。对于我们的体内模型，我们研究了年轻健康的人类志愿者，其中大部分是白人和男性；当这些受试者在低盐饮食中达到平衡以激活肾素系统时，研究了肾灌注对肾素系统药物中断的反应。通过这种方法，我们研究了 3 种 ACE 抑制剂、2 种肾素抑制剂和 2 种 Ang II 拮抗剂在各自剂量反应关系顶部的肾血管扩张剂反应。当这些研究开始时，我们的前提是激肽依赖性机制有助于肾血流动力学对 ACE 抑制的反应；因此，肾血管扩张剂对 ACE 抑制的反应将超过替代方案。令我们惊讶的是，所研究的两种肾素抑制剂和两种血管紧张素II拮抗剂均诱导了140至150 mL/min/1.73 m(2)的肾血管舒张反应，比ACE抑制的最大肾血流动力学反应（90至100 mL/min/1.73 m(2)）大约大50%。根据体外系统的数据，我们的研究结果表明，在完整的人肾中，几乎所有 Ang II 的生成都是肾素依赖性的，但至少 40% 的 Ang I 通过 ACE 以外的途径（可能是食糜酶）转化为 Ang II，尽管存在其他酶途径。初步数据表明，在糖尿病等疾病状态下，非 ACE 通路可能要大得多。这些研究的意义之一是，在组织水平上，Ang II 拮抗剂比 ACE 抑制剂具有更大的阻断肾素-血管紧张素系统的潜力，这对治疗具有重要意义。
Multiple lines of evidence have suggested that alternative pathways to the angiotensin-converting enzyme (ACE) exists for angiotensin II (Ang II) generation in the heart, large arteries, and the kidney. In vitro studies in intact tissues, homogenates, or membrane isolates from the heart and large arteries have repeatedly demonstrated such pathways, but the issue remains unresolved because the approaches used have not made it possible to extrapolate from the in vitro to the in vivo situation. For our in vivo model, we studied young and healthy human volunteers, for the most part white and male; when these subjects achieved balance on a low salt diet to activate the renin system, the response of renal perfusion to pharmacological interruption of the renin system was studied. With this approach, we studied the renal vasodilator response to 3 ACE inhibitors, 2 renin inhibitors, and 2 Ang II antagonists at the top of their respective dose-response relationships. When these studies were initiated, our premise was that a kinin-dependent mechanism contributed to the renal hemodynamic response to ACE inhibition; therefore, the renal vasodilator response to ACE inhibition would exceed the alternatives. To our surprise, both renin inhibitors and both Ang II antagonists that were studied induced a renal vasodilator response of 140 to 150 mL/min/1.73 m(2), approximate to 50% larger than the maximal renal hemodynamic response to ACE inhibition, which was 90 to 100 mL/min/1.73 m(2). In light of the data from in vitro systems, our findings indicate that in the intact human kidney, virtually all Ang II generation is renin-dependent but at least 40% of Ang I is converted to Ang II by pathways other than ACE, presumably a chymase, although other enzyme pathways exist. Preliminary data indicate that the non-ACE pathway may be substantially larger in disease states such as diabetes mellitus. One implication of the studies is that at the tissue level, Ang II antagonists have much greater potential for blocking the renin-angiotensin system than does ACE inhibition-with implications for therapeutics.