Low-dose Aspirin and Human Skin Blood Flow

小剂量阿司匹林与人体皮肤血流

基本信息

批准号：
8115086
负责人：
Lacy M. ALEXANDER
金额：
$ 18.43万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115086
关键词：
ADP Receptors Academy Accounting Acute Adrenergic Agents American Aspirin Attenuated Blinded Blood Platelets Blood Vessels Blood Viscosity Blood flow Body Temperature Cardiovascular system Chest Chronic Cross-Over Studies Cutaneous Data Dehydration Disease Dose Environment Enzymes Exercise Gold Grant Heat Losses Heat Stress Disorders Heating Hour Human Impairment Intervention Iontophoresis Laboratories Life Manuscripts Outcome Pathway interactions Pharmaceutical Preparations Physicians Placebo Control Placebos Platelet Inhibitors Preparation Primary Prevention Production Property Prostaglandin-Endoperoxide Synthase Publishing Receptor Inhibition Reflex action Research Research Design Risk Factors Secondary Prevention Signal Transduction Site Skin Stimulus Thromboxane A2 Time Vascular Endothelial Cell Vasoconstrictor Agents Vasodilation Whole Blood Woman adrenergic cardiovascular disorder risk clopidogrel cyclooxygenase 1 men middle age pressure public health relevance reactive hyperemia response shear stress viscoelasticity

项目摘要

DESCRIPTION (provided by applicant): Daily low-dose aspirin (81 mg) therapy is the gold standard for primary and secondary prevention of atherothrombotic disease. The American Academy of Chest Physicians recommends that all men over 45 and women over 50 with e1 cardiovascular disease risk factor engage in low-dose aspirin therapy1. Aspirin is an irreversible inhibitor of platelet and vascular cyclooxygenase (COX) I and II. At low doses aspirin acetylates platelet COX-1 in the presystemic (portal) circulation2 inhibiting platelet production of the potent aggregating agent and vasoconstrictor thromboxane A2 (TXA2) for the life of the platelet (~10 days). Our recently published data [and manuscript currently in preparation] demonstrate that platelet inhibition with either chronic low-dose aspirin (81mg daily) or clopidogrel 1) consistently and significantly attenuates reflex cutaneous vasodilation (VD) in middle-aged (5813 years) human skin3; however the precise mechanisms underlying these responses are unclear as are the functional consequences, if any. Considering the widespread use of low-dose aspirin and other platelet inhibitors, and the unexpected potential for these therapies to impair thermoregulatory VD, further research into the underlying vascular signaling mechanisms is needed. Our newly published data show that vascular inhibition of COX is not the mechanisms by which low-dose aspirin is attenuating reflex VD. Furthermore, our preliminary data shows that significantly attenuated reflex VD occurs regardless of the mechanisms of platelet inhibition (low-dose aspirin platelet COX-1 or clopidogrel platelet ADP-receptor). There are several putative mechanisms that may explain our observations including: 1) platelets may release substances that directly stimulate cutaneous VD pathways during reflex cutaneous VD, and/or 2) decreased whole blood viscoelasticity induced by platelet inhibitors may decrease the shear stimulus on the cutaneous microvasculature resulting in attenuated VD. The studies presented in this proposal systematically characterize the mechanisms and functional effects of changing whole blood viscoelastic properties on cutaneous vasodilatory responsiveness using a several stimuli to alter microvascular shear (cutaneous reactive hyperemia and slow local heating). [We aim to independently alter whole blood viscosity while inducing cutaneous VD via shear-stress mechanisms with and without the localized sympathetic adrenergic control intact (bretylium iontophoresis).] Finally, we will examine potential functional consequences of asprin/clopidogril-induced impairments in thermoregulatory effector mechanisms during exercise in the heat. PUBLIC HEALTH RELEVANCE: Daily low-dose aspirin (81 mg) is the gold standard antiplatelet therapy for primary and secondary prevention of atherothrombotic disease. Data from our laboratory suggest that chronic low-dose aspirin therapy (81mg daily for > 1year) severely attenuates reflex cutaneous vasodilation in middle-aged human skin (5813 years). Our research could uncover a previously undocumented effect of aspirin and other platelet inhibitors on the control of cutaneous vasodilation and thus on the ability to regulate core body temperature during heat stress. This finding would be important to the many people routinely taking daily low-dose aspirin and their physicians. Also, the project will examine the mechanisms underlying the effect of these drugs to further our understanding of the control of skin blood flow and the decrement in the cutaneous vasodilation response to heat stress observed in older people.

描述（由申请人提供）：每日低剂量阿司匹林（81 毫克）治疗是动脉粥样硬化血栓性疾病一级和二级预防的金标准。美国胸科医师学会建议，所有具有 e1 心血管疾病危险因素的 45 岁以上男性和 50 岁以上女性均应接受低剂量阿司匹林治疗1。阿司匹林是血小板和血管环氧合酶 (COX) I 和 II 的不可逆抑制剂。低剂量的阿司匹林会乙酰化体前（门静脉）循环中的血小板 COX-1，从而在血小板的生命周期（约 10 天）内抑制血小板产生强效聚集剂和血管收缩剂血栓素 A2 (TXA2)。我们最近发表的数据[和目前正在准备的手稿]表明，长期低剂量阿司匹林（每天 81 毫克）或氯吡格雷 1）的血小板抑制作用一致且显着减弱中年（5813 岁）人类皮肤的反射性皮肤血管舒张（VD）3 ;然而，这些反应背后的确切机制尚不清楚，功能性后果（如果有的话）也不清楚。考虑到低剂量阿司匹林和其他血小板抑制剂的广泛使用，以及这些疗法损害体温调节性 VD 的意想不到的潜力，需要进一步研究潜在的血管信号传导机制。我们新发表的数据表明，COX 的血管抑制并不是低剂量阿司匹林减弱反射性 VD 的机制。此外，我们的初步数据表明，无论血小板抑制机制如何（低剂量阿司匹林血小板 COX-1 或氯吡格雷血小板 ADP 受体），反射性 VD 都会发生显着减弱。有几种可能的机制可以解释我们的观察结果，包括：1) 血小板可能会在反射性皮肤 VD 过程中释放直接刺激皮肤 VD 通路的物质，和/或 2) 血小板抑制剂引起的全血粘弹性降低可能会减少对皮肤的剪切刺激。微血管系统导致 VD 减弱。本提案中提出的研究系统地描述了改变全血粘弹性特性对皮肤血管舒张反应性的机制和功能影响，使用几种刺激来改变微血管剪切力（皮肤反应性充血和缓慢的局部加热）。 [我们的目标是独立改变全血粘度，同时通过剪切应力机制诱导皮肤 VD，有或没有完整的局部交感肾上腺素能控制（溴苄离子电渗疗法）。]最后，我们将检查阿司匹林/氯吡格利诱导的体温调节损伤的潜在功能后果高温运动期间的效应机制。公共卫生相关性：每日低剂量阿司匹林（81 毫克）是动脉粥样硬化血栓性疾病一级和二级预防的金标准抗血小板治疗。我们实验室的数据表明，长期低剂量阿司匹林治疗（每天 81 毫克，持续 > 1 年）会严重减弱中年人类皮肤（5813 岁）的反射性皮肤血管舒张。我们的研究可能会揭示阿司匹林和其他血小板抑制剂对控制皮肤血管舒张的影响，从而对热应激期间调节核心体温的能力产生影响，这一作用此前未被记录。这一发现对于许多每天服用低剂量阿司匹林的人及其医生来说很重要。此外，该项目还将研究这些药物作用的机制，以进一步了解老年人皮肤血流的控制和皮肤血管舒张对热应激反应的减弱。