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

项目概要 百分之二十的美国人一生中会患上心力衰竭。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受体阻滞剂的作用， 和盐皮质激素受体拮抗剂对死亡率、心力衰竭患者的五年预期寿命的影响 是百分之五十。 2015 年，FDA 批准了 LCZ696 (Entresto™)，一种 ARB 缬沙坦和 沙库巴曲（sacubitril），一种脑啡肽酶（中性肽链内切酶-24.11）抑制剂前药，与 LCZ696 相比，死亡率降低 在一项随机临床试验中，对患有心力衰竭、射血分数降低和射血分数增加的患者进行依那普利治疗 循环脑钠尿肽 (BNP) 或 N 末端 (NT) proBNP。 LCZ696 还减少了再住院率 急性失代偿性心力衰竭。然而，LCZ696在临床实践中尚未得到充分利用，并且 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。脑啡肽酶可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。在心脏中 对于失败的患者，LCZ696 会增加 BNP（一种脑啡肽酶底物），同时减少非脑啡肽酶底物 NT-proBNP，表明 LCZ696 增强利钠肽的作用。另一方面，利钠 与缓激肽和 P 物质相比，肽是脑啡肽酶的不良底物，而缓激肽和 P 物质可以具有有益的作用 对血压、利尿、尿钠排泄、纤维蛋白溶解和重塑的影响，但也会产生不良反应 如低血压和血管性水肿。我们的研究小组在研究贡献方面拥有丰富的经验 肽类药物可抑制血管肽酶，如 ACE、二肽基肽酶 4 (DPP4) 和脑啡肽酶。在这个 根据提议，我们测试了缓激肽有助于血管扩张、血压和肾功能的总体假设 联合血管紧张素受体阻断/脑啡肽酶抑制的作用。在目标 1 中，我们将检验以下假设： 与单独使用缬沙坦相比，LCZ696 增强了动脉内缓激肽、P 物质或 BNP 的作用。 我们将在存在和不存在 DPP4 抑制剂的情况下检验这一假设，因为它可能会增强 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降低血压的假设， LCZ696 在心力衰竭患者的起始和滴定过程中的利尿钠和利尿作用 缓激肽 B2 受体拮抗剂。在目标3中，我们将探讨内源性物质P对效应的贡献 使用 P 物质 (NK1) 受体拮抗剂的 LCZ696。在综合目标 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定的方法测量） 质谱分析），以及预测 LCZ696 血压反应的 NEP 活性。这些研究 将提供有关联合血管紧张素受体阻断作用机制的新信息 脑啡肽酶抑制，并产生新的策略，以最大限度地减少不利影响，同时最大限度地提高有益影响 这种有前途的新型心力衰竭药物的研究。

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.