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（由应用提供）：二肽基肽酶IV（DPP4）抑制剂是口服可用的抗糖尿病药物，可通过防止增加胰岛素的降解（如胰甘氨酸肽1和胃抑制性肽）降解血糖。预计到2017年，全球DPP4抑制剂市场已达到101亿美元。糖尿病患者的心血管死亡风险增加。肾素 - 血管紧张素系统（RAS）的中断减少了糖尿病患者的心血管事件和心脏病的风险。在检查DPP4抑制剂心血管效应的临床试验中，超过80％的患者正在服用血管紧张素转化酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARBS）。了解DPP4抑制剂和抑制药物的RAS的相互作用性心血管效应至关重要。除了防止降解增加外，DPP4抑制剂还可以防止其他倒数氨基末端精氨酸或脯氨酸（包括ACE底物底物P）降解。在ACE抑制期间，DPP4降解的物质P的增加。抑制DPP4和ACE物质在啮齿动物中的潜在影响。物质P会导致血管舒张和血管通透性，但也刺激了神经末端的去甲肾上腺素和DPP4底物神经肽Y（NPY）的释放。通过物质P的交感神经激活可能会删除高血压和心力衰竭的影响。我们发现DPP4抑制与ACE抑制之间存在血流动力学相互作用，这可能会减少ACE抑制剂的有益心血管效应。具体而言，我们发现DPP4抑制作用降低了对急性最大ACE抑制的血压反应，并增加了代谢综合征患者的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，动脉内物质P会刺激去甲肾上腺素的血管释放。我们建议测试DPP4抑制作用通过内源性物质P增加慢性ACE抑制的抗高血压抑制作用P.在AIM 1中，我们将测试DPP4抑制作用的假说可减少型号抑制型临床抗体，但在AIM上抑制了2PP4抑制作用，但在AIM 1中抑制了2PP4的抗性性，但对型号抑制型的抗高血压效应，但对型号抑制型的抗高血压效应。我们将评估内源性物质P使用P（NK1）受体阻滞剂偶然的物质抑制DPP4和ACE抑制的影响。在AIM 2中，我们将检验以下假设：PESTESS P会在组合DPP4组合过程中通过NK1受体依赖性机制增加Norepinephrine的溢出和NPY的净血管释放，并在2型糖尿病患者中抑制ACE。在AIM 3中，我们将检验以下假设：DPP4抑制也可以防止NPY降解，从而导致糖尿病患者的血管收缩增加和前臂去甲肾上腺素。这些研究的结果可能会影响数百万糖尿病患者和高血压的治疗。