Nawarskas J, Rajan V, Frishman W H
Department of Pharmacy, University of New Mexico, Albuquerque, NM, USA.
Heart Dis. 2001 Nov-Dec;3(6):378-85. doi: 10.1097/00132580-200111000-00006.
Vasopeptidase inhibitors represent a new class of cardiovascular drugs. They function as a combined angiotensin-converting enzyme (ACE) inhibitor and neutral endopeptidase (NEP) inhibitor, the latter of which potentiates the actions of atrial natriuretic peptide (ANP) by minimizing its degradation in the circulation. The consequence of such dual inhibition is a synergistic reduction of vasoconstriction and enhancement of vasodilation, thereby serving to more effectively reduce blood pressure. Furthermore, inhibition of the renin-angiotensin-aldosterone system (RAAS) prevents physiologic compensatory responses in vivo seen with NEP inhibition alone. Vasopeptidase inhibitors have also shown to potentiate bradykinin and adrenomedullin, which additionally contribute to cardiovascular regulation. The most extensively researched and promising agents within the class of VP inhibitors is omapatrilat, a mercaptoacyl derivative of a bicyclic thiazepinone dipeptide. It is a single molecule with equal potency and affinity for ACE and NEP inhibition. Although ACE inhibition tends to more selectively benefit high-renin models of hypertension, vasopeptidase inhibition has been shown to be equally efficacious in low-, normal-, and high-renin models. Contrary to NEP inhibition alone, omapatrilat has also demonstrated the ability to significantly reduce blood pressure in spontaneously hypertensive rats, the equivalent of essential hypertension in humans. Studies also suggest that omapatrilat has cardioprotective properties, especially in the setting of congestive heart failure. More specifically, animal models have demonstrated omapatrilat to be more effective than ACE inhibition alone in remodeling the heart and improving its contractile function. Human studies have documented the efficacy of omapatrilat in the treatment of both hypertension and, to a lesser extent, heart failure. Safety concerns (specifically angioedema) are currently being addressed before the widespread utilization of this promising new agent.
血管肽酶抑制剂是一类新型心血管药物。它们兼具血管紧张素转换酶（ACE）抑制剂和中性内肽酶（NEP）抑制剂的功能，后者通过减少心房利钠肽（ANP）在循环中的降解来增强其作用。这种双重抑制的结果是协同降低血管收缩并增强血管舒张，从而更有效地降低血压。此外，抑制肾素-血管紧张素-醛固酮系统（RAAS）可防止单独抑制NEP时在体内出现的生理代偿反应。血管肽酶抑制剂还显示出可增强缓激肽和肾上腺髓质素的作用，这也有助于心血管调节。血管肽酶抑制剂类中研究最广泛且最具前景的药物是奥帕曲拉，它是一种双环噻氮酮二肽的巯基酰基衍生物。它是一种对ACE和NEP抑制具有同等效力和亲和力的单一分子。尽管ACE抑制往往更选择性地有益于高肾素型高血压模型，但血管肽酶抑制在低肾素、正常肾素和高肾素模型中均显示出同等疗效。与单独抑制NEP相反，奥帕曲拉在自发性高血压大鼠（相当于人类的原发性高血压）中也显示出显著降低血压的能力。研究还表明奥帕曲拉具有心脏保护特性，尤其是在充血性心力衰竭的情况下。更具体地说，动物模型已证明奥帕曲拉在心脏重塑和改善其收缩功能方面比单独的ACE抑制更有效。人体研究已证明奥帕曲拉在治疗高血压以及在较小程度上治疗心力衰竭方面的疗效。在广泛使用这种有前景的新药之前，目前正在解决安全问题（特别是血管性水肿）。
