Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition

项目摘要 在美国，有20%的人会在一生中患上心力衰竭。尽管有益 血管紧张素转换酶（ACE）抑制剂、血管紧张素受体阻滞剂（ARB）、β受体阻滞剂 和盐皮质激素受体拮抗剂对死亡率的影响， 是百分之五十。2015年，FDA批准了LCZ 696（Entresto™），这是一种ARB缬沙坦和 沙库巴曲，一种脑啡肽酶（中性内肽酶-24.11）抑制剂前体药物，与对照组相比， 在心力衰竭、射血分数降低和射血分数升高的患者中， 循环脑利钠肽（BNP）或N-末端（NT）proBNP。LCZ 696还减少了患者的再住院治疗， 急性失代偿性心力衰竭然而，LCZ 696在临床实践中未得到充分利用， 对低血压的担忧阻碍了使用。联合ARB和 脑啡肽酶抑制剂降低血压的作用尚不完全清楚。脑啡肽酶降解许多血管活性肽 包括利钠肽、血管紧张素（Ang）I和II、内皮素、缓激肽和P物质。 失败的患者，LCZ 696增加脑啡肽酶底物BNP，同时减少非脑啡肽酶底物 NT-proBNP，表明LCZ 696增强利钠肽的作用。另一方面，利钠利尿剂 与缓激肽和P物质相比，肽是脑啡肽酶的不良底物，其可以具有有益的生物学效应。 对血压、利尿、利钠、纤维蛋白溶解和重塑的影响，但也导致不良反应 比如低血压和血管性水肿我们的研究小组在研究以下方面的贡献方面有丰富的经验： 从肽到抑制血管肽酶的药物，如ACE、二肽基肽酶-4（DPP 4）和脑啡肽酶。在这 我们的建议，我们测试的首要假设，缓激肽有助于血管扩张，血压和肾脏 血管紧张素受体阻断剂/脑啡肽酶抑制剂的联合作用。在目标1中，我们将检验以下假设： 与单独缬沙坦相比，LCZ 696增强动脉内缓激肽、P物质或BNP的作用。 我们将在存在和不存在DPP 4抑制剂的情况下测试这一假设，因为它可能增强DPP 4抑制剂的作用。 脑啡肽酶抑制在目标2中，我们将检验内源性缓激肽有助于水肿的假设， 在心力衰竭患者中使用LCZ 696在开始和向上滴定期间的利钠和利尿作用， 缓激肽B2受体拮抗剂。在目标3中，我们将探讨内源性P物质对效应的贡献。 LCZ 696使用物质P（NK 1）受体拮抗剂。在合并目标2和3中，我们将评估 个体患者因素，如种族、性别、BNP（通过临床免疫测定和特异性免疫测定测量）、 质谱测定）和预测对LCZ 696的血压响应的NEP活性。这些研究 将提供关于联合血管紧张素受体阻滞剂作用机制的新信息， 脑啡肽酶抑制，并导致新的策略，以尽量减少不利影响，同时最大限度地发挥有益作用 这类很有前途的治疗心力衰竭的新药。

PROJECT SUMMARY Twenty percent of people in the United States will develop heart failure during their lives. Despite beneficial effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, and mineralocorticoid receptor antagonists on mortality, the five-year life expectancy of a patient with heart failure is fifty percent. In 2015, the FDA approved LCZ696 (Entresto™), a molecular complex of the ARB valsartan and sacubitril, a neprilysin (neutral endopeptidase-24.11) inhibitor prodrug, after LCZ696 reduced mortality compared to enalapril in a randomized clinical trial in patients with heart failure, reduced ejection fraction, and increased circulating brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. LCZ696 also reduces rehospitalization in acutely decompensated heart failure. Nevertheless, LCZ696 has been underutilized in clinical practice, and concerns regarding hypotension have impeded use. The mechanism(s) through which the combined ARB and neprilysin inhibitor reduces blood pressure are not fully known. Neprilysin degrades many vasoactive peptides including the natriuretic peptides, angiotensins (Ang) I and II, endothelins, bradykinin, and substance P. In heart failure patients, LCZ696 increases BNP, a neprilysin substrate, while decreasing the non-neprilysin substrate NT-proBNP, suggesting that LCZ696 potentiates effects of the natriuretic peptide. On the other hand, natriuretic peptides are poor substrates for neprilysin compared to bradykinin and substance P, which can have beneficial effects on blood pressure, diuresis, natriuresis, fibrinolysis and remodeling but also contribute to adverse effects like hypotension and angioedema. Our research group has extensive experience studying the contribution of peptides to drugs that inhibit vasopeptidases such as ACE, dipeptidyl peptidase-4 (DPP4), and neprilysin. In this proposal, we test the overarching hypothesis that bradykinin contributes to vasodilator, blood pressure and renal effects of combined angiotensin receptor blockade/neprilysin inhibition. In Aim 1, we will test the hypothesis that LCZ696 potentiates the effects of intra-arterial bradykinin, substance P, or BNP compared to valsartan alone. We will test this hypothesis in the presence and absence of a DPP4 inhibitor, as it may enhance effects of neprilysin inhibition. In Aim 2, we will test the hypothesis that endogenous bradykinin contributes to hypotensive, natriuretic and diuretic effects of LCZ696 during initiation and up-titration in heart failure patients using a bradykinin B2 receptor antagonist. In Aim 3, we will probe the contribution of endogenous substance P to effects of LCZ696 using a substance P (NK1) receptor antagonist. In the combined Aims 2 and 3, we will assess individual patient factors such as race, gender, BNP (measured both by clinical immunoassay and by specific mass spectrometric assay), and NEP activity that predict blood pressure response to LCZ696. These studies will provide novel information about the mechanism(s) of action of combined angiotensin receptor blockade and neprilysin inhibition, and lead to new strategies to minimize adverse effects while maximizing beneficial effects of this promising new class of drugs for heart failure.