Pharmacologic interruption of the renin-angiotensin system.
Pharmacologic interruption of the renin-angiotensin system.
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肾素-血管紧张素系统的药理学中断。
DOI：
10.1146/annurev.pa.19.040179.003015
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发表时间：
1979
影响因子：
12.5
通讯作者：
N. Hollenberg
中科院分区：
文献类型：
--
作者：
N. Hollenberg
1959 年，在影响平滑肌和血管的多肽研讨会上，埃利奥特讲述了在阐明十肽血管紧张素 I 的结构后，他如何着手合成该药物，并发现尽管化学成分非常相似，但合成产物对大鼠血压的活性只有血管紧张素 II 的约 1% (l)。埃利奥特在演讲中的要点是羧基末端氨基酸苯丙氨酸含有几乎相等的 0 型和 L 型混合物。考虑到研讨会的自由度，他继续做出了大胆而敏锐的推测：“含有邻苯丙氨酸的肽在体内充当高血压素的强大抑制剂。”他指出，证据需要明确合成含有纯邻苯丙氨酸的肽，并表示希望很快就能实现。不幸的是，这种合成从未被报道过，并且羧基末端氨基酸对于开发血管紧张素拮抗剂的重要性显然被遗忘了十多年。考虑到肾素-血管紧张素系统的药理学中断对于剖析血管紧张素在生理学和病理生理学中的作用的潜在重要性，在血管紧张素的演讲之后的讨论未能对埃利奥特的新建议作出反应是令人惊讶的，也许是令人沮丧的。 1970 年，两个小组分别是 Khairallah、Bumpus 和他们在克利夫兰诊所基金会 (Cleve Land Clinic Foundation) 的同事，以及 8t 的 Marshall、Vine 和 Needleman。路易斯
In 1 959, at a symposium on polypeptides that affect smooth muscle and blood vessels, Elliott recounted how, following elucidation of the structure of the decapeptide, angiotensin I, he set out to synthesize the agent and found that the synthetic product had only about I % of the activity of angiotensin II on rat blood pressure despite close chemical resemblance ( l). Elliott's key point in his talk was that the carboxy terminal amino acid, phenylalanine, contained almost equal mixtures of the 0and L-forms. Given the freedom of a symposium setting, he went on to make the daring and perceptive speculation that "the peptide containing o-phenylalanine was acting as a powerful inhibitor of hypertensin in vivo." He pointed out that proof required the unequivocal synthesis of a peptide containing pure o-phenylalanine, and expressed the hope that this would soon be achieved. Unfortunately, that synthesis was never reported and the importance of the carboxy terminal amino acid for the development of angiotensin antagonists was apparently forgotten for over a decade. Given the potential importance of pharmacologic interruption of the renin-angiotensin system in dissecting angiotensin'S role in physiology and pathophysiology, the failure of the discussion that followed the presentations on angiotensin to respond to Elliott's novel suggestion was surprising, and perhaps discouraging. In 1 970 two groups, Khairallah, Bumpus, and their colleagues at Cleve land Clinic Foundation and Marshall, Vine & Needleman in 8t. Louis