Cardiovascular Consequences of Peptidase Inhibition

肽酶抑制的心血管后果

• 批准号: 9257457
• 负责人: Nancy J. Brown
• 金额: $ 46.34万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/9257457
• 关键词: Acute; Acute Coronary Event; 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; Data; Diabetes Mellitus; Dipeptidyl Peptidases; 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; Kidney Failure; Lead; Metabolic syndrome; Microvascular Dysfunction; Myocardial Infarction; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Oral; 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; aprepitant; base; cardiovascular risk factor; diabetes risk; diabetic; enzyme substrate; glucagon like peptide; glucagon-like peptide; glucagon-like peptide 1; heart disease risk; hemodynamics; inhibitor/antagonist; macrovascular disease; neuropeptide Y; peptide analog; personalized strategies; prevent; public health relevance; randomized placebo controlled trial; receptor; response; standard of care; thrombolysis; treatment strategy; vasoconstriction

 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（由申请人提供）： 二肽基肽酶 IV (DPP4) 抑制剂是口服抗糖尿病药，通过防止肠降血糖素（如胰高血糖素样肽 1 和抑胃肽）的降解来降低血糖。预计到 2017 年，DPP4 抑制剂的全球市场将达到 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) 的中断可减少糖尿病患者的心血管事件和心脏病风险。在检查 DPP4 抑制剂对心血管影响的临床试验中，超过 80% 的患者正在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 抑制药物对心血管的相互作用至关重要。 除了防止肠降血糖素降解外，DPP4 抑制剂还可防止其他具有倒数第二个氨基末端的精氨酸或脯氨酸的肽的降解，包括 ACE 底物 P 物质。在 ACE 抑制期间，DPP4 降解的 P 物质比例增加。 DPP4 和 ACE 的抑制可增强 P 物质对啮齿动物的作用。 P 物质会引起血管舒张和血管通透性，但也会刺激神经末梢释放去甲肾上腺素和 DPP4 底物神经肽 Y (NPY)。 P 物质激活交感神经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 抑制会降低代谢综合征患者对急性最大 ACE 抑制的血压反应，并增加心率和循环去甲肾上腺素。此外，我们发现，当 DPP4 和 ACE 均受到抑制时，动脉内 P 物质会刺激血管释放去甲肾上腺素。 我们建议检验这一总体假设，即 DPP4 抑制通过增加内源性 P 物质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，我们将检验以下假设：在 2 型糖尿病患者中，DPP4 抑制会降低慢性 ACE 抑制的抗高血压作用，但不会降低血管紧张素受体阻断的抗高血压作用。我们将评估 使用 P 物质 (NK1) 受体阻滞剂阿瑞匹坦联合抑制 DPP4 和 ACE 时，内源性 P 物质的作用。在目标 2 中，我们将检验以下假设：在 2 型糖尿病患者联合 DPP4 和 ACE 抑制期间，P 物质通过 NK1 受体依赖性机制增加去甲肾上腺素溢出和 NPY 的净血管释放。在目标 3 中，我们将检验这样的假设：DPP4 抑制还可以防止 NPY 降解，从而导致糖尿病患者的血管收缩和前臂去甲肾上腺素溢出增加。 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。