Cardiovascular Consequences of Peptidase Inhibition

 说明(申请人提供)：二肽基肽酶IV(DPP4)抑制剂是一种口服的抗糖尿病药物，通过防止胰升糖素样肽1和胃抑制肽等内分泌的降解来降低血糖。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)可降低糖尿病和心脏病患者的心血管风险。在最近两项检测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DPP4抑制对血管紧张素转换酶抑制的血流动力学反应有交互作用，这可能会降低血管紧张素转换酶抑制剂的心脏保护作用。具体地说，我们发现DPP4抑制减弱了对急性最大血管紧张素转换酶抑制的降压反应，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抑制的降压效应的总体假设。在目标1中，我们将测试DPP4抑制减弱2型糖尿病患者对慢性ACE抑制的降压反应的假说，但不是血管紧张素受体阻滞剂。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，我们将验证这一假说，即在2型糖尿病患者中，P物质通过NK1受体依赖的机制同时抑制DPP4和ACE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。这项提案的结果可能会对数百万2型糖尿病患者的治疗产生影响。

 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.