Timmermans P B, Duncia J V, Carini D J, Chiu A T, Wong P C, Wexler R R, Smith R D
Discovery Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19800-0400, USA.
J Hum Hypertens. 1995 Nov;9 Suppl 5:S3-18.
The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT1-subtype receptors; and (3) losartan as a specific probe for exploring the multiple roles of angiotensin II (Ang II) in normal physiology and pathologic states. Losartan is the first nonpeptide orally active Ang II receptor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan has been widely used to define the distribution and function of AT receptor subtypes. Although possible roles of the AT2 subtype have been reported, virtually all of the known effects of Ang II are blocked by losartan. Specific AT1 receptor blockade has been broadly compared with ACE inhibition. Possible differences on the basis of AT1 selectivity, bradykinin potentiating effects and Ang II formed by non-ACE pathways are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and the Ang II-induced cardiovascular 'growth' in vitro and in vivo. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, like ACE inhibition, markedly reduced the elevation in blood pressure, proteinuria or sclerosis. In aortocaval shunt, coronary ligation and ventricular pacing models of heart failure, losartan demonstrated a pathological role for Ang II by reversing the associated haemodynamic findings. In SHR-stroke prone, losartan dramatically increased survival while having a limited effect on blood pressure, suggesting a non-pressure dependent effect of Ang II. These collective data show that Ang II exerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clinical trials with patients with heart failure.
氯沙坦的“发现”代表了三个不同的发现：（1）氯沙坦作为独特的联苯四唑分子以及新化学类别的首个药物；（2）氯沙坦作为识别AT1亚型受体的工具；（3）氯沙坦作为探索血管紧张素II（Ang II）在正常生理和病理状态下多种作用的特异性探针。氯沙坦是首个进入临床试验的非肽类口服活性Ang II受体拮抗剂。选择氯沙坦是因其对Ang II受体的亲和力、对Ang II的功能拮抗作用、缺乏激动剂特性以及口服抗高血压作用。氯沙坦已被广泛用于确定AT受体亚型的分布和功能。尽管已报道了AT2亚型的可能作用，但实际上Ang II的所有已知作用都可被氯沙坦阻断。特异性AT1受体阻断已与ACE抑制作用进行了广泛比较。讨论了基于AT1选择性、缓激肽增强作用以及非ACE途径形成的Ang II的可能差异。氯沙坦在体外和体内均可阻断Ang II的血管收缩作用、Ang II诱导的醛固酮合成和/或释放以及Ang II诱导的心血管“生长”。在各种实验性高血压模型中，氯沙坦可预防或逆转血压升高及相关的心血管肥大，这与ACE抑制剂相似。同样，在肾衰竭模型（如肾质量减少、嘌呤霉素、赭曲霉毒素）中，氯沙坦与ACE抑制作用一样，可显著降低血压升高、蛋白尿或硬化程度。在心力衰竭的主动脉腔静脉分流、冠状动脉结扎和心室起搏模型中，氯沙坦通过逆转相关的血流动力学结果，证明了Ang II的病理作用。在易发生中风的SHR中，氯沙坦显著提高了生存率，而对血压的影响有限，这表明Ang II具有非压力依赖性作用。这些综合数据表明，Ang II在血管、心脏、肾脏和脑部疾病的实验模型中发挥着复杂病理作用。氯沙坦在心力衰竭实验模型中的有效性支持了其在心力衰竭患者临床试验中的评估。
