Low-dose Aspirin and Human Skin Blood Flow

描述(申请人提供)：每日小剂量阿司匹林(81毫克)治疗是动脉粥样硬化性血栓形成疾病一级和二级预防的黄金标准。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，如果有心血管疾病的危险因素，都应该服用低剂量的阿司匹林。阿司匹林是一种不可逆的血小板和血管环氧合酶(COX)I和II的抑制物。在低剂量时，阿司匹林在收缩前(门脉)循环中使血小板COX-1乙酰化2，在血小板的寿命(~10天)内抑制这种有效的聚集剂和血管收缩因子血栓素A2(TXA2)的产生。我们最近发表的数据[和目前正在准备中的手稿]表明，慢性低剂量阿司匹林(每天81毫克)或氯吡格雷1)抑制血小板持续并显著减轻中年(5813岁)人皮肤的反射性皮肤血管扩张(VD)3；然而，这些反应的确切机制尚不清楚，如果有的话，其功能后果也是如此。考虑到小剂量阿司匹林和其他血小板抑制剂的广泛使用，以及这些疗法意想不到的损害体温调节性VD的潜力，需要对潜在的血管信号机制进行进一步研究。我们最新发表的数据表明，COX的血管抑制不是小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(小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。有几种可能的机制可以解释我们的观察结果，包括：1)在反射性皮肤VD过程中，血小板可能释放直接刺激皮肤VD通路的物质，和/或2)由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，从而导致VD减弱。这项研究系统地描述了通过几种刺激改变微血管切变(皮肤反应性充血和局部缓慢加热)来改变全血粘弹性特性对皮肤血管扩张反应的机制和功能效应。[我们的目标是独立改变全血粘度，同时通过剪应力机制在交感肾上腺素能控制完好的情况下诱发皮肤血管性痴呆(Bretylium离子导入)。]最后，我们将研究在高温下运动时，阿司匹林/氯吡格利诱导的体温调节效应器机制损伤的潜在功能后果。 公共卫生相关性：每日小剂量阿司匹林(81毫克)是一级和二级预防动脉粥样硬化性血栓疾病的金标准抗血小板疗法。来自我们实验室的数据表明，慢性小剂量阿司匹林疗法(每天81毫克，持续1年)严重减弱中年人皮肤的反射性皮肤血管扩张(5813岁)。我们的研究可能会揭示阿司匹林和其他血小板抑制剂在控制皮肤血管扩张，从而在热应激期间调节核心体温的能力方面以前未见文献报道的效果。这一发现对许多每天常规服用低剂量阿司匹林的人和他们的医生来说都很重要。此外，该项目还将研究这些药物的作用机制，以进一步了解在老年人中观察到的皮肤血流量的控制和皮肤血管扩张反应的减弱。

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.