Eberhardt R T, Kevak R M, Kang P M, Frishman W H
Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461.
J Clin Pharmacol. 1993 Nov;33(11):1023-38. doi: 10.1002/j.1552-4604.1993.tb01939.x.
Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
通过血管紧张素II（AII）的多种作用，肾素-血管紧张素系统（RAS）参与心血管稳态。血管紧张素II通过与特定的膜结合受体结合而起作用，这些受体与几种信号转导途径之一偶联。这些AII受体表现出异质性，以AT1和AT2受体亚型为代表。AT1受体介导RAS的主要心血管作用。该受体已从多个物种中克隆出来，揭示了与跨膜G蛋白偶联受体一致的特征。通过克隆AT1受体的同种型，进一步证明了AII受体的异质性。阻断AII与其受体的相互作用是抑制RAS作用的最直接位点。许多AII受体拮抗剂，包括AII的肽类似物和针对AII的抗体，具有不利的特性，限制了它们的临床应用。然而，具有AII拮抗剂特性和良好特性的咪唑化合物的发现和进一步开发，有望用于临床。该领域的领先药物是选择性AT1受体拮抗剂氯沙坦（以前称为DuP 753或MK-954）。氯沙坦被证明是许多AII诱导作用的有效拮抗剂，并且在许多高血压（HTN）动物模型中是有效的抗高血压药物。氯沙坦在预防中风、治疗充血性心力衰竭（CHF）以及延缓动物模型中肾病进展方面也显示出次要益处。临床研究证实了氯沙坦的AII拮抗剂作用，并表明氯沙坦将有效治疗原发性HTN。AII拮抗作用可能在原发性HTN和CHF中提供有用的治疗，已知RAS在这些疾病中起主要作用。正如血管紧张素转换酶（ACE）抑制在治疗或预防许多其他疾病中的潜在有用性所表明的那样，AII拮抗作用的效用可能超出HTN和CHF的范围。AII拮抗剂相对于ACE抑制剂的关键优势在于，它们可以避免与后者药物的缓激肽增强相关的不良副作用。AII拮抗剂将有助于确定RAS在生理调节和各种疾病状态的病理生理学中的作用。
