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

ARB/NEP 抑制引起低血压反应的机制

基本信息

批准号：
9884685
负责人：
Nancy J. Brown
金额：
$ 71.09万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9884685
关键词：
Acute Adrenergic beta-Antagonists Adverse effects Affect Alteplase Aminopeptidase P Angioneurotic Edema Angiotensin I Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Antidiabetic Drugs Antihypertensive Agents Atrial Natriuretic Factor Biological Assay Blood Pressure Blood flow Bradykinin Bradykinin B2 Receptor Brain natriuretic peptide C-Type Natriuretic Peptide Catecholamines Cessation of life Chemicals Clinical Complex Diabetes Mellitus Diagnosis Dipeptidyl Peptidases Diuresis Diuretics Dose Drug Interactions EFRAC Enalapril Endothelin Endothelium FDA approved Fiber Fibrinolysis Forearm Gender Grant Heart Heart failure Hospitalization Hypotension Immunoassay Investigational Drugs Kidney Kidney Failure Label Lead Life Expectancy Measures Medicine Mineralocorticoid Receptor Molecular Morbidity - disease rate N-terminal Natriuresis Natriuretic Peptides Neprilysin Patients Peptides Peptidyl-Dipeptidase A Pharmaceutical Preparations Prevalence Prodrugs Race Randomized Clinical Trials Receptor, Angiotensin, Type 1 Renin-Angiotensin-Aldosterone System Research Sensory Substance P Substance P Receptor Testing Titrations Treatment Failure United States Vascular Permeabilities Vasodilation Vasodilator Agents Work aprepitant base blood pressure reduction cardiovascular pharmacology clinical practice experience hemodynamics hospital readmission icatibant improved individual patient inhibitor/antagonist mortality novel novel drug class novel therapeutics peptide P prevent prospective receptor response saluretic side effect valsartan

项目摘要

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.

项目摘要在美国，有20％的人将在他们的一生中发展心力衰竭。尽管有益血管紧张素转化酶（ACE）抑制剂，血管紧张素受体阻滞剂（ARB），β受体阻滞剂，和矿物皮质激素受体拮抗剂关于死亡率，这是心力衰竭患者的五年预期寿命是百分之五十。 2015年，FDA批准了LCZ696（Entresto™），这是ARB Valsartan的分子络合物和 Sacubitril，Neprilysin（中性内肽酶-24.11）抑制剂前药，LCZ696降低死亡率降低了在心力衰竭，射血分数降低并增加的患者的随机临床试验中启用ablelolin 循环的脑发脂肽（BNP）或N末端（NT）概率。 LCZ696还减少心力衰竭敏锐的。然而，LCZ696在临床实践中未充分利用，对低血压的担忧阻碍了使用。 ARB和ARB合并的机制 Neprilysin抑制剂降低血压尚不清楚。 Neprilysin降解了许多血管活性肽包括亚钠肽，血管紧张素（ANG）I和II，内皮蛋白，松曲蛋白和物质P。失败患者LCZ696增加了BNP，是Neprilysin底物的BNP，同时降低了非静脉脂蛋白底物 NT-proBNP，表明LCZ696增强了脂肪胡椒的作用。另一方面，纳特里尔特与Bradykinin和底物P相比对血压，利尿，纳地尿，纤维蛋白溶解和重塑的影响，但也会导致不良反应像低血压和血管性水肿。我们的研究小组有丰富的研究经验抑制血管肽酶，例如ACE，二肽基肽-4（DPP4）和Neprilysin的药物。在这个提案，我们检验了整个假设，即心动激肽有助于血压和肾脏有助于血压和肾脏血管紧张素受体阻滞/Neprilysin抑制的影响。在AIM 1中，我们将检验以下假设 LCZ696与单独的瓦尔萨坦相比，动脉内平息，物质P或BNP的影响。我们将在存在和不存在DPP4抑制剂的情况下检验该假设，因为它可能会增强 Neprilysin抑制。在AIM 2中，我们将检验以下假设：内源性心动激肽有助于降低，降低， LCZ696在启动期间的纳地尿作用和利尿作用，使用A的心力衰竭患者使用A 心动激肽B2受体拮抗剂。在AIM 3中，我们将探测内源物质P对影响的贡献 LCZ696使用P（NK1）受体拮抗剂的物质。在联合目标2和3中，我们将评估种族，性别，BNP等个体患者因素（通过临床免疫测定和特定质谱分析）和NEP活性，可预测对LCZ696的血压反应。这些研究将提供有关联合血管紧张素受体阻滞和作用机制的新信息 Neprilysin抑制，并导致新的策略，以最大程度地减少不良影响，同时最大化有益效果在这种有前途的新药物中，用于心力衰竭。