Renin inhibition in hypertension
Renin inhibition in hypertension
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DOI：
10.1016/j.jacc.2007.10.027
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发表时间：
2008-02-05
影响因子：
24
通讯作者：
Kad, Rishi
中科院分区：
文献类型：
--
作者：
Gradman, Alan H.;Kad, Rishi
50年前，研究人员确定肾素抑制为阻断肾素-血管紧张素系统的首选药理学方法。肾素是一种单特异性酶，催化血管紧张素II合成中的限速步骤。当肾素和原肾素与（原）肾素受体结合时，会发生放大的酶活性和额外的生理效应。直到最近，临床上有效的肾素抑制剂的开发仍然难以捉摸。分子建模被用来开发阿利吉仑，一种有效的，低分子量，非肽，直接的肾素抑制剂，具有足够的生物利用度，口服给药后产生持续抑制血浆肾素活性。在高血压患者中，阿利吉仑产生剂量依赖性血压（BP）降低和24小时BP控制，剂量高达约300 mg，每日一次;在这些剂量下，阿利吉仑显示出安慰剂样的耐受性。其抗高血压的效力与血管紧张素受体阻滞剂、血管紧张素转换酶抑制剂和利尿剂大致相当。突然停药后，观察到持续的血压降低和血浆肾素活性的长期抑制。当与利尿剂联合使用时，可观察到完全叠加的BP降低。当与血管紧张素受体阻滞剂同时给药时，阿利吉仑可显著降低血压，这表明其药理作用互补，并可更完全地阻断肾素-血管紧张素系统。目前正在进行临床试验，评估阿利吉仑联合血管紧张素受体阻滞剂对终末器官损伤的中间标志物的影响，并计划进行长期终点试验。这些研究的结果将最终确定肾素抑制剂和阿利吉仑在治疗高血压和相关心血管疾病中的地位。阿利吉仑对受体结合的肾素和原肾素的影响是积极研究的主题。
Fifty years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiological effects occur when renin and pro-renin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive. Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of plasma renin activity after oral administration. In patients with hypertension, aliskiren produces dose-dependent blood pressure (BP) reduction and 24-h BP control up to a dose of approximately 300 mg once daily; at these doses, aliskiren shows placebo-like tolerability. Its anti hypertensive potency is approximately equivalent to that of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics. After abrupt withdrawal, persistent BP reduction and prolonged suppression of plasma renin activity is observed. When combined with diuretics, fully additive BP reduction is seen. When given with an anglotensin receptor blocker, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. Clinical trials are currently underway assessing the effects of aliskiren combined with an angiotensin receptor blocker on intermediate markers of end organ damage, and long-term end point trials are planned. The results of these studies will ultimately determine the place of renin inhibition and aliskiren in the treatment of hypertension and related cardiovascular disorders. The effect of aliskiren on receptor-bound renin and pro-renin is the subject of active investigation.