Cardiovascular Consequences of Peptidase Inhibition

 描述（由申请人提供）：二肽基肽酶IV（DPP 4）抑制剂是一种口服抗糖尿病药物，通过防止胰高血糖素样肽1和胃抑制肽等内分泌物降解来降低血糖。据预测，到2017年，DPP 4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。干扰肾素-血管紧张素系统（RAS）可降低糖尿病和心脏病患者的心血管风险。在最近的两项研究DPP 4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DPP 4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的降解外，DPP 4抑制剂还防止具有倒数第二个氨基末端精氨酸或脯氨酸的其他肽的降解，包括ACE底物物质P。在ACE抑制期间，增加的P物质比例被DPP 4降解。抑制DPP 4和ACE增强P物质在啮齿动物中的作用。P物质引起血管舒张和血管通透性，但也刺激去甲肾上腺素和DPP 4底物神经肽Y（NPY）从神经末梢释放。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。我们已经发现了DPP 4抑制对ACE抑制的血流动力学反应的交互作用，这可能会降低ACE抑制剂的心脏保护作用。具体地说，我们已经发现，DPP 4抑制减弱了对急性最大ACE抑制的抗高血压反应，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DPP 4和ACE都被抑制时，动脉内P物质刺激血管释放去甲肾上腺素。我们建议测试的首要假设，即DPP 4抑制减弱慢性ACE抑制的抗高血压作用，通过增加激活的交感神经系统的内源性物质P。在目的1，我们将测试的假设，即DPP 4抑制减弱慢性ACE抑制的抗高血压反应，而不是血管紧张素受体阻滞剂，在2型糖尿病患者。我们将评估 内源性P物质对使用P物质（NK 1）受体阻断剂阿瑞匹坦联合抑制DPP 4和ACE的作用的贡献。在目标2中，我们将测试的假设，即P物质增加去甲肾上腺素溢出和净血管释放的NPY通过NK 1受体依赖性机制，同时抑制DPP 4和ACE在2型糖尿病患者。在目标3中，我们将检验这样的假设，即DPP 4抑制也阻止了NPY的降解，导致糖尿病患者血管收缩和前臂去甲肾上腺素溢出增加。这项提案的结果可能会影响数百万2型糖尿病患者的治疗。

 DESCRIPTION (provided by applicant): Dipeptidyl peptidase IV (DPP4) inhibitors are orally available anti-diabetic agents that decrease blood glucose by preventing the degradation of incretions' 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 risk in patients with diabetes and heart disease. In two recent 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 an interactive effect of DPP4 inhibition on the hemodynamic response to ACE inhibition that may reduce the cardioprotective effect of ACE inhibitors. Specifically we have found that DPP4 inhibition attenuates the antihypertensive 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 DPP4 and ACE are both 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 attenuates the anti-hypertensive response to 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 concurrent inhibition of DPP4 and ACE 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. The results of this proposal could impact on the treatment of millions of patients with type 2 diabetes.