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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（81mg）治疗是动脉粥样硬化性血栓形成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45岁以上的男性和50岁以上有心血管疾病危险因素的女性接受低剂量阿司匹林治疗。阿司匹林是血小板和血管环氧化酶（COX） I和II的不可逆抑制剂。在低剂量阿司匹林乙酰化血小板COX-1在系统前（门脉）循环2抑制血小板产生的强效聚集剂和血管收缩剂血栓素A2 （TXA2）的血小板寿命（~10天）。我们最近发表的数据[和目前正在准备的手稿]表明，慢性低剂量阿司匹林（每天81mg）或氯吡格雷(1)的血小板抑制作用持续且显著地减弱中年（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，功能后果也不清楚，如果有的话。考虑到低剂量阿司匹林和其他血小板抑制剂的广泛使用，以及这些疗法损害热调节性VD的意想不到的潜力，需要进一步研究潜在的血管信号机制。我们新发表的数据表明，血管抑制COX不是低剂量阿司匹林减弱反射性VD的机制。此外，我们的初步数据显示，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都会显著减弱。有几种推测的机制可以解释我们的观察结果，包括：1)血小板在反射性皮肤VD时可能释放直接刺激皮肤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减少对皮肤微血管的剪切刺激，导致VD减弱。本研究系统地描述了通过几种刺激改变微血管剪切（皮肤反应性充血和局部缓慢加热），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。[我们的目标是独立地改变全血粘度，同时通过剪切应力机制诱导皮肤VD，有或没有局部交感肾上腺素能控制完整（溴化锂离子导入）。]最后，我们将研究阿司匹林/氯吡格雷在高温运动中引起的热调节效应机制损伤的潜在功能后果。