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.

 说明(申请人提供)：二肽基肽酶IV(DPP4)抑制剂是口服的抗糖尿病药物，通过防止胰岛素降解，如胰高血糖素样肽1和胃抑制肽来降低血糖。据预测，到2017年，全球DPP4抑制剂市场将达到101亿美元。糖尿病患者心血管死亡的风险增加。阻断肾素-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。在检测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抑制药物的相互作用的心血管效应是至关重要的。除了防止降解素的降解外，DPP4抑制剂还可以防止具有倒数第二个氨基末端的精氨酸或Pro的其他多肽的降解，包括ACE底物P物质。在ACE抑制过程中，P物质的比例增加被DPP4降解。抑制DPP4和ACE可增强P物质对啮齿动物的作用。P物质引起血管扩张和血管通透性，但也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在高血压和心力衰竭中产生有害影响。我们发现了DPP4抑制和ACE抑制之间的血流动力学相互作用，这可能会减少ACE抑制剂对心血管的有益影响。具体地说，我们发现DPP4抑制降低了对急性最大ACE抑制的血压反应，并提高了代谢综合征患者的心率和循环去甲肾上腺素。此外，我们还发现，当DPP4和ACE均被抑制时，动脉内P物质可刺激血管释放去甲肾上腺素。我们建议验证最主要的假设，即DPP4抑制通过增加内源性物质P对交感神经系统的激活而减弱慢性ACE抑制的降压效果。在目标1中，我们将测试DPP4抑制降低2型糖尿病患者慢性ACE抑制的降压效果的假说，而不是血管紧张素受体阻滞剂的降压效果。我们将评估 内源性P物质在P物质(NK1)受体阻滞剂联合抑制DPP4和ACE中的作用。在目标2中，我们将验证一种假设，即在DPP4和ACE联合抑制2型糖尿病患者的过程中，P物质通过NK1受体依赖的机制增加去甲肾上腺素溢出和NPY的血管净释放。在目标3中，我们将测试DPP4抑制也可以阻止NPY降解的假设，这会导致糖尿病患者血管收缩增加和前臂去甲肾上腺素溢出。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。