Trindade P T, Rouleau J L
Cardiology Center, University Hospital Geneva, Geneva, Switzerland.
Heart Fail Monit. 2001;2(1):2-7.
Current thinking views the progression of heart failure as the result of sustained activation of vasoconstrictor neurohormones. In this model, the sustained synthesis of vasoconstrictor neurohormones leads to disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse ventricular remodeling through myocyte cell loss and progressive myocardial fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-adrenergic and the renin-angiotensin-aldosterone systems. Although the observed decrease in mortality using this strategy in heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of vasodilator neurohormones, deserve stimulation. It is known a family of vasodilator neurohormones - the natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These peptides are degraded primarily by a neutral endopeptidase (NEP), an endothelial cell-surface zinc metallopeptidase, which shares a similar structure and catalytic site with the angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide, but also bradykinin and adrenomedullin. The recognition that ACE and NEP enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as vasopeptidase inhibitors. Preliminary clinical trials in heart failure with vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing vasodilator substances, holds promise as a valuable option in heart failure treatment for the near future.
目前的观点认为，心力衰竭的进展是血管收缩神经激素持续激活的结果。在这个模型中，血管收缩神经激素的持续合成通过心肌细胞结构和功能的改变导致疾病进展，这会影响心肌收缩力、心脏代谢和细胞生长。最终，这些事件通过心肌细胞丢失和进行性心肌纤维化诱导不可逆的不良心室重塑。在过去十年中，几项具有里程碑意义的临床试验通过针对β-肾上腺素能和肾素-血管紧张素-醛固酮系统的激活来检验神经激素假说。尽管在心力衰竭人群中使用这种策略观察到的死亡率下降令人鼓舞，但发病率和死亡率水平仍然很高，现在已经表明，其他几种体液相互作用也在起作用，可能值得拮抗，或者就血管舒张神经激素而言，值得刺激。已知一类血管舒张神经激素——利钠肽——具有利钠、血管舒张和抗增殖作用，可内源性抑制肾素-血管紧张素系统。这些肽主要由中性内肽酶（NEP）降解，NEP是一种内皮细胞表面锌金属肽酶，与血管紧张素转换酶（ACE）具有相似的结构和催化位点。NEP具有广泛的底物特异性，包括心房利钠肽、脑利钠肽和C型利钠肽，还包括缓激肽和肾上腺髓质素。认识到ACE和NEP酶具有相关结构，导致设计和开发了一类对ACE和NEP具有双重抑制作用的分子，称为血管肽酶抑制剂。血管肽酶抑制剂治疗心力衰竭的初步临床试验已经开展，并显示出有希望的结果。因此，通过减弱过度的血管收缩和增强血管舒张物质来联合抑制ACE和NEP，有望在不久的将来成为心力衰竭治疗的一个有价值的选择。
