Low-dose Aspirin and Human Skin Blood Flow

描述（由申请人提供）：每日低剂量阿司匹林（81 mg）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45岁以上的男性和50岁以上的女性，有e1心血管疾病风险因素的人，都应接受低剂量阿司匹林治疗。阿司匹林是血小板和血管环氧合酶（考克斯）I和II的不可逆抑制剂。在低剂量阿司匹林乙酰化血小板考克斯-1在前系统（门静脉）循环2抑制血小板生产的有效的凝聚剂和血管收缩剂血栓素A2（TXA 2）的生命血小板（约10天）。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（每日81 mg）或氯吡格雷1）抑制血小板可持续并显著减弱中年人（58 - 13岁）皮肤的反射性皮肤血管舒张（VD）3;然而，这些反应的确切机制尚不清楚，功能后果也不清楚。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的意外可能性，需要进一步研究潜在的血管信号传导机制。我们最新发表的数据表明，血管抑制考克斯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考克斯-1或氯吡格雷血小板ADP受体），都会发生明显减弱的反射VD。有几种假定的机制可以解释我们的观察结果，包括：1）在反射性皮肤VD期间，血小板可能释放直接刺激皮肤VD途径的物质，和/或2）血小板抑制剂诱导的全血粘弹性降低可能降低对皮肤微血管系统的剪切刺激，导致VD减弱。本提案中提出的研究系统地表征了改变全血粘弹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（皮肤反应性充血和缓慢局部加热）。[We目的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，有和没有局部交感肾上腺素能控制完整（溴苄铵离子电渗疗法）。最后，我们将研究阿司匹林/氯吡格雷诱导的损伤在热运动过程中的体温调节效应机制的潜在功能后果。 公共卫生相关性：每日低剂量阿司匹林（81 mg）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 mg，持续> 1年）严重减弱中年人皮肤（58 - 13岁）的反射性皮肤血管舒张。我们的研究可以揭示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热应激期间调节核心体温的能力的先前未记录的作用。这一发现对许多日常服用低剂量阿司匹林的人和他们的医生都很重要。此外，该项目将研究这些药物的作用机制，以进一步了解皮肤血流的控制和老年人对热应激的皮肤血管舒张反应的减少。

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.