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.