Cardiovascular Consequences of Peptidase Inhibition

肽酶抑制的心血管后果

基本信息

批准号：
8960866
负责人：
Nancy J. Brown
金额：
$ 44.41万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960866
关键词：
Acute Adult Affect Agonist Alcohol or Other Drugs use Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Antidiabetic Drugs Antihypertensive Agents Arginine Attenuated Blood Glucose Blood Pressure Blood Vessels C Fiber Cardiovascular system Caring Cessation of life Chronic Clinical Treatment Clinical Trials Coronary Data Diabetes Mellitus Dipeptidyl-Peptidase IV Dose Drug usage Enzyme Inhibition Event Forearm Gastric Inhibitory Polypeptide Glucose Heart Diseases Heart Rate Heart failure Hospitalization Hypertension Hypoglycemia Individual Injury Interruption Kidney Kidney Diseases Lead Marketing Metabolic syndrome Microvascular Dysfunction Myocardial Myocardial Infarction Nerve Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Outcome Patients Peptide Hydrolases Peptides Peptidyl-Dipeptidase A Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Placebos Prevalence Proline Publishing Receptor Inhibition Receptor, Angiotensin, Type 1 Recording of previous events Renin-Angiotensin System Reporting Retinal Diseases Risk Risk Factors Rodent Stroke Substance P Sulfonylurea Compounds Sympathetic Nervous System Testing Time Vascular Permeabilities Vasodilation Weight Gain analog aprepitant base cardiovascular risk factor diabetes risk diabetic enzyme substrate glucagon-like peptide glucagon-like peptide 1 heart disease risk hemodynamics inhibitor/antagonist neuropeptide Y prevent public health relevance randomized placebo controlled trial receptor response standard of care thrombolysis treatment strategy vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Dipeptidyl peptidase IV (DPP4) inhibitors are orally available antidiabetic agents that decrease blood glucose by preventing the degradation of incretins such as glucagon-like peptide 1 and gastric inhibitory peptide. The global market for DPP4 inhibitors has been forecast to reach $10.1 billion by the year 2017. Diabetics are at increased risk of cardiovascular death. Interruption of the renin-angiotensin system (RAS) reduces cardiovascular events in patients with diabetes and risk of heart disease. In clinical trials examining the cardiovascular effects of DPP4 inhibitors, over eighty percent of patients were taking angiotensin- converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Understanding the interactive cardiovascular effects of DPP4 inhibitors and RAS inhibiting drugs is of the utmost importance. In addition to preventing degradation of incretins, DPP4 inhibitors prevent degradation of other peptides with a penultimate amino-terminus arginine or proline, including the ACE substrate substance P. During ACE inhibition, an increased proportion of substance P is degraded by DPP4. Inhibition of both DPP4 and ACE potentiates effects of substance P in rodents. Substance P causes vasodilation and vascular permeability, but also stimulates release of norepinephrine and the DPP4 substrate neuropeptide Y (NPY) from nerve terminals. Sympathetic activation by substance P could have deleterious effects in hypertension and heart failure. We have discovered a hemodynamic interaction between DPP4 inhibition and ACE inhibition that may reduce the beneficial cardiovascular effects of ACE inhibitors. Specifically, we have found that DPP4 inhibition decreases the blood pressure response to acute maximal ACE inhibition and increases heart rate and circulating norepinephrine in individuals with the metabolic syndrome. In addition, we have found that intra- arterial substance P stimulates vascular release of norepinephrine when both DPP4 and ACE are inhibited. We propose to test the overarching hypothesis that DPP4 inhibition attenuates the antihypertensive effect of chronic ACE inhibition by increasing activation of the sympathetic nervous system by endogenous substance P. In Aim 1, we will test the hypothesis that DPP4 inhibition decreases the anti-hypertensive effect of chronic ACE inhibition, but not angiotensin receptor blockade, in patients with type 2 diabetes. We will assess the contribution of endogenous substance P to the effects of combined DPP4 and ACE inhibition using the substance P (NK1) receptor blocker aprepitant. In Aim 2, we will test the hypothesis that substance P increases norepinephrine spillover and net vascular release of NPY through an NK1 receptor-dependent mechanism during combined DPP4 and ACE inhibition in individuals with type 2 diabetes. In Aim 3, we will test the hypothesis that DPP4 inhibition also prevents the degradation of NPY, leading to increased vasoconstriction and forearm norepinephrine spillover in diabetics. Results of these studies could affect treatment of millions of people with diabetes and high blood pressure.

描述（申请人提供）：二肽基肽酶 IV (DPP4) 抑制剂是口服抗糖尿病药，通过防止胰高血糖素样肽 1 和抑胃肽等肠降血糖素的降解来降低血糖。 DPP4 抑制剂的全球市场已被预测。到 2017 年将达到 101 亿美元。糖尿病患者心血管死亡的风险增加。肾素-血管紧张素系统 (RAS) 可减少糖尿病患者的心血管事件和心脏病风险。在检查 DPP4 抑制剂心血管作用的临床试验中，超过 80% 的患者服用血管紧张素转换酶 (ACE) 抑制剂或血管紧张素受体阻滞剂。 (ARB)。了解 DPP4 抑制剂和 RAS 抑制药物的相互作用对心血管的影响至关重要。除了防止肠降血糖素降解外，DPP4 抑制剂还可以防止其他药物降解。倒数第二个氨基末端有精氨酸或脯氨酸的肽，包括 ACE 底物 P 物质。在 ACE 抑制过程中，DPP4 降解的 P 物质比例增加。DPP4 和 ACE 的抑制都会增强 P 物质在啮齿类动物中的作用。血管舒张和血管通透性，还刺激交感神经末梢释放去甲肾上腺素和 DPP4 底物神经肽 Y (NPY)。 P 物质的激活可能对高血压和心力衰竭产生有害影响。我们发现 DPP4 抑制和 ACE 抑制之间存在血流动力学相互作用，可能会降低 ACE 抑制剂对心血管的有益作用。具体来说，我们发现 DPP4 抑制会降低血压反应。急性最大 ACE 抑制并增加代谢综合征个体的心率和循环去甲肾上腺素。此外，我们发现，当 DPP4 和 DPP4 都存在时，动脉内 P 物质会刺激血管释放去甲肾上腺素。我们建议检验以下总体假设：DPP4 抑制通过增加内源性物质 P 对交感神经系统的激活来减弱慢性 ACE 抑制的抗高血压作用。在目标 1 中，我们将检验 DPP4 抑制会降低抗高血压作用的假设。 - 慢性 ACE 抑制而非血管紧张素受体阻断对 2 型糖尿病患者的高血压作用我们将进行评估。使用 P 物质 (NK1) 受体阻滞剂阿瑞吡坦，内源性 P 物质对 DPP4 和 ACE 联合作用的贡献在目标 2 中，我们将检验以下假设：P 物质通过增加去甲肾上腺素溢出抑制和 NPY 的净血管释放。 2 型糖尿病患者联合 DPP4 和 ACE 抑制期间的 NK1 受体依赖性机制在目标 3 中，我们将检验 DPP4 抑制也能阻止 NPY 降解的假设，从而导致 NPY 降解。这些研究的结果可能会影响数百万糖尿病和高血压患者的治疗。