Siegl P K, Kivlighn S D, Broten T P
Merck Research Laboratories, Pharmacology Department, West Point, PA 19486, USA.
J Hypertens Suppl. 1995 Jul;13(1):S15-21. doi: 10.1097/00004872-199507001-00002.
Clinical experience with angiotensin converting enzyme (ACE) inhibitors has shown that inhibition of the renin-angiotensin system is effective therapy for hypertension and heart failure. Losartan (DuP753, MK954, cozaar) is the first non-peptidic drug that inhibits the renin-angiotensin system by selectively blocking the interaction of angiotensin II with its receptor.
Pharmacological differences between ACE inhibitors and losartan could affect comparative efficacy and/or safety. In addition to angiotensin I, ACE has other substrates (e.g. kinins). Blocking the metabolism of kinins with ACE inhibitors could be beneficial (e.g. vasodilation) and/or elicit side effects (e.g. cough) which will not be produced by losartan. Non-ACE pathways of angiotensin II formation have been described (e.g. angiotensin I convertase) which may limit the ability of ACE inhibitors to prevent formation of angiotensin II in all tissues. Losartan blocks angiotensin II responses irrespective of the route or site of angiotensin II formation. Two binding sites for angiotensin II are widely accepted, AT1 and AT2. Losartan blocks only AT1 sites while ACE inhibitors functionally block angiotensin II interaction with both sites. Since the physiological role for AT2 sites is unknown, the relevance of this difference between ACE inhibitors and losartan is questionable.
In animal models of hypertension, the efficacy of losartan is equivalent to the efficacy of ACE inhibitors. In animal models that reflect complications of hypertension, such as kidney dysfunction, cardiac and vascular hypertrophy and stroke, losartan and ACE inhibitors are also equally effective. From these results, kinin potentiation and lack of inhibition of angiotensin I convertase do not lead to differences in pharmacological efficacy between ACE inhibitors and losartan. Therefore, with respect to therapeutic efficacy, results in animal models indicate that losartan will display the beneficial pharmacology of ACE inhibitors without the detrimental side effects attributed to kinin potentiation.
血管紧张素转换酶（ACE）抑制剂的临床经验表明，抑制肾素-血管紧张素系统是治疗高血压和心力衰竭的有效方法。氯沙坦（DuP753、MK954、科素亚）是首个通过选择性阻断血管紧张素II与其受体的相互作用来抑制肾素-血管紧张素系统的非肽类药物。
氯沙坦与ACE抑制剂的差异：ACE抑制剂与氯沙坦之间的药理学差异可能会影响比较疗效和/或安全性。除血管紧张素I外，ACE还有其他底物（如激肽）。用ACE抑制剂阻断激肽的代谢可能有益（如血管舒张）和/或引发副作用（如咳嗽），而氯沙坦不会产生这些副作用。已描述了血管紧张素II形成的非ACE途径（如血管紧张素I转换酶），这可能会限制ACE抑制剂在所有组织中阻止血管紧张素II形成的能力。氯沙坦可阻断血管紧张素II的反应，而不论血管紧张素II的形成途径或部位如何。血管紧张素II有两个广泛认可的结合位点，即AT1和AT2。氯沙坦仅阻断AT1位点，而ACE抑制剂在功能上阻断血管紧张素II与两个位点的相互作用。由于AT2位点的生理作用尚不清楚，ACE抑制剂与氯沙坦之间这种差异的相关性值得怀疑。
在高血压动物模型中，氯沙坦的疗效与ACE抑制剂相当。在反映高血压并发症的动物模型中，如肾功能障碍、心脏和血管肥大以及中风，氯沙坦和ACE抑制剂同样有效。从这些结果来看，激肽增强和血管紧张素I转换酶未受抑制并不会导致ACE抑制剂与氯沙坦在药理疗效上产生差异。因此，就治疗效果而言，动物模型的结果表明，氯沙坦将展现出ACE抑制剂的有益药理学特性，而不会出现归因于激肽增强的有害副作用。
