Timmermans P B, Wong P C, Chiu A T, Herblin W F, Smith R D
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
J Hum Hypertens. 1993 Aug;7 Suppl 2:S19-31.
The 'angiotensin system' is expressed at the whole body, organ/tissue and cellular levels through the action of angiotensin II at specific receptors. An appreciation of the full scope of the actions of angiotensin II (endocrine, paracrine and autocrine) has been made possible by the discovery of the non-peptide angiotensin II receptor antagonists, losartan (DuP 753/MK954)(AT1-selective) and PD123177 (AT2-selective). Virtually all of the known effects of angiotensin II are blocked by losartan and designated AT1. Selective AT1 receptor blockade with losartan lowers BP in angiotensin II-dependent models of hypertension, reduces cardiac hypertrophy, improves haemodynamics in models of cardiac failure and reduces the intimal response to vascular injury. AT2 sites have been localised in distinct parts of the brain and in foetal tissue. The functional role of the AT2 sites remains controversial, but possible roles in neuronal ion channel function and collagen metabolism in fibroblasts have been reported. AT1 (losartan-sensitive) receptor subtypes have now been cloned from several rat tissues, suggesting that selective agents of the future may be even more specifically targeted. New perspectives in the control of the angiotensin system continue to evolve rapidly as the new receptor antagonists and molecular biology techniques expand our understanding of angiotensin II.
“血管紧张素系统”通过血管紧张素II作用于特定受体，在全身、器官/组织及细胞水平表达。非肽类血管紧张素II受体拮抗剂氯沙坦（DuP 753/MK954，AT1选择性）和PD123177（AT2选择性）的发现，使人们得以全面了解血管紧张素II的作用范围（内分泌、旁分泌和自分泌）。血管紧张素II的几乎所有已知作用都可被氯沙坦阻断，并被认定为AT1介导。在依赖血管紧张素II的高血压模型中，用氯沙坦选择性阻断AT1受体可降低血压，减轻心脏肥大，改善心力衰竭模型中的血流动力学，并减轻血管损伤后的内膜反应。AT2位点已定位在脑的不同部位和胎儿组织中。AT2位点的功能作用仍存在争议，但已有报道称其在神经元离子通道功能和成纤维细胞胶原代谢中可能发挥作用。现已从几种大鼠组织中克隆出AT1（对氯沙坦敏感）受体亚型，这表明未来的选择性药物可能具有更特异的靶向性。随着新型受体拮抗剂和分子生物学技术拓展我们对血管紧张素II的认识，血管紧张素系统调控方面的新观点仍在迅速演变。
