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 mg）治疗是预防动脉粥样硬化性疾病的原发性和次要预防的黄金标准。美国胸部医师学会建议所有45岁以上的男性和50岁以上的E1心血管疾病危险因素从事低剂量阿司匹林治疗1。阿司匹林是血小板和血管环氧酶（COX）I和II的不可逆抑制剂。在低剂量的情况下，阿司匹林乙酰酸酯乙酰酸血小板Cox-1中的（门户网站）循环2抑制血小板寿命（约10天）的血小板产生有效聚集剂和血管收缩型血栓烷A2（TXA2）。我们最近发表的数据[和目前正在准备的手稿]表明，在中年（5813年）的人类Skin3中，始终如一地抑制血小板抑制慢性低剂量阿司匹林（每天81mg）或氯吡格雷1）始终如一地减弱反射皮肤血管散发（VD）；但是，这些反应的基础机制尚不清楚，如果有的话，功能后果也是如此。考虑到广泛使用低剂量阿司匹林和其他血小板抑制剂，以及这些疗法会损害体温调节VD的意外潜力，因此需要进一步研究基础的血管信号传导机制。我们新发表的数据表明，COX的血管抑制不是低剂量阿司匹林抑制反射VD的机制。此外，我们的初步数据表明，无论血小板抑制的机制如何（低剂量阿司匹官阿司匹林血小板COX-1或氯吡格雷血小板ADP受体受体），反射VD显着减弱。有几种推定的机制可以解释我们的观察结果，包括：1）血小板可能释放出反射皮肤VD期间直接刺激皮肤VD途径的物质，和/或2）降低了由血小板抑制剂诱导的全血粘弹性的降低，可能会降低皮肤微血管上的剪切刺激，从而降低可伸缩的vD。该提案中提出的研究系统地表征了改变全血粘弹性特性对皮肤血管舒张反应的机制和功能效应，该反应性使用几种刺激来改变微血管剪切（皮肤反应性充血性高血症和局部加热）。 [我们的目标是通过有或没有局部交感神经肾上腺素能控制完整的剪切压力机制诱导皮肤VD，同时独立改变全血粘度（Bretylium离子电池）。公共卫生相关性：每日低剂量阿司匹林（81 mg）是用于预防动脉粥样硬化性疾病的原发性和次要预防的金标准抗血小板疗法。我们实验室的数据表明，慢性低剂量阿司匹林治疗（每天为81mg，> 1年）严重减弱了中年人皮肤的反射性皮肤血管舒张（5813年）。我们的研究可能会发现阿司匹林和其他血小板抑制剂对皮肤血管舒张的控制以及在热应激期间调节核心体温的能力的先前无证作用。这一发现对许多通常服用每日低剂量阿司匹林及其医生的人很重要。此外，该项目将研究这些药物作用的基础机制，以进一步了解对皮肤血流的控制以及对老年人观察到的热应激的皮肤血管舒张反应的减少。