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

项目总结 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心力衰竭患者死亡率、预期寿命的影响 是50%。2015年，FDA批准了Arb valsartan和Arb valsartan的分子络合物LCZ696(Entresto™)。 舒必利，一种奈普利辛(中性内肽酶-24.11)抑制剂前药，LCZ696后降低死亡率的比较 依那普利在心力衰竭患者的随机临床试验中，降低了射血分数，增加了 循环脑利钠肽(BNP)或N末端(NT)proBNP。LCZ696还减少了 严重失代偿性心力衰竭。然而，LCZ696在临床实践中一直没有得到充分利用，而且 对低血压的担忧阻碍了它的使用。ARB和ARB结合的机制(S) 奈普利辛抑制剂降低血压的作用尚不完全清楚。奈普利辛可降解多种血管活性多肽 包括利钠肽、血管紧张素(Ang)I和II、内皮素、缓激肽和P物质。 衰竭患者，LCZ696增加脑钠素底物，同时减少非脑纤溶素底物 NT-proBNP，提示LCZ696增强了利钠肽的作用。另一方面，利钠药 与缓激肽和P物质相比，多肽是neprilysin的较差底物，这可能有好处 对血压、利尿、利钠、纤溶和重塑的影响，但也会造成不良影响 比如低血压和血管水肿。我们的研究小组有丰富的经验研究 抑制血管肽酶的药物，如血管紧张素转换酶、二肽基肽酶-4(DPP4)和奈普利辛。在这 提案中，我们检验了缓激肽对血管扩张剂、血压和肾脏有贡献这一重要假设。 血管紧张素受体拮抗剂/奈普利辛联合应用的效果。在目标1中，我们将检验假设 与单独使用valsartan相比，LCZ696可增强动脉内注射缓激肽、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 Neprilysin抑制。在目标2中，我们将检验内源性缓激肽有助于降压的假设， LCZ696在心力衰竭患者起效和上滴定过程中的利钠利尿作用 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 使用P物质(NK1)受体拮抗剂。在综合目标2和目标3中，我们将评估 个别患者的因素，如种族、性别、BNP(通过临床免疫分析和特定的 质谱分析)和NEP活性预测对LCZ696的血压反应。这些研究 将为血管紧张素受体拮抗剂联合应用的作用机制(S)提供新的信息。 抑制Neprilysin，并导致新的策略，以最大限度地减少不利影响，同时最大化有益的影响 这一前景看好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.