PLATELET INVOLVEMENT IN REFLEX CUTANEOUS VASODILATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 由于非一氧化氮(NO)和NO依赖机制的减少，在高温期间，人类的衰老与减弱的皮肤血管扩张(VD)有关。初步数据显示，用于预防动脉粥样硬化性血栓形成疾病的标准阿司匹林疗法严重减弱了中年人皮肤的反射性皮肤血管扩张(58？3岁)。阿司匹林治疗可能会抑制血小板和血管组织中的COX亚型，从而阻断与VD有关的一种关键酶。或者，热应激过程中的血小板激活可能会释放一些物质，这些物质参与了导致血管性痴呆的途径。我们将使用全身干预措施(小剂量阿司匹林和/或血小板抑制剂，氯吡格利硫酸氢盐)，结合对一氧化氮合酶和环氧合酶衍生的血管扩张剂的局部检查，来研究血小板和血管COX在反射性VD中的作用。 假设1：小剂量阿司匹林(81毫克)将通过COX依赖机制减弱反射性皮肤血管扩张。 假设2：用硫酸氢氯吡格雷特异性抑制血小板不会减弱反射性皮肤血管扩张。 筛查后，受试者接受基线测试(不含口服药物)，包括皮肤微渗析(MD)、全身加热和激光多普勒血流计。在测试过程中，将在皮肤中放置四个皮内微透析探头。微透析部位被指定为药物处理，作为对照、一氧化氮合酶抑制(NOS-I)、环氧合酶(COX-I)抑制(COX-I)以及一氧化氮合酶和环氧合酶(NOS-I)抑制(COX-I)。然后，受试者进入双盲交叉设计研究，服用81毫克阿司匹林和/或75毫克氯吡格雷(Plavix)。受试者服用每种药物7天，然后在开始服用另一种药物之前进行2周的冲洗。分析包括三向重复测量方差分析。在SAS中执行Proc混合过程。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human aging is associated with attenuated cutaneous vasodilation (VD) during hyperthermia due to a reduction in non-nitric oxide (NO)- and NO-dependent mechanisms. Preliminary data suggest that standard aspirin therapy for prevention of atherothrombotic disease severely attenuates reflex cutaneous vasodilation in middle-aged human skin (58¿3 years). Aspirin therapy may inhibit COX isoforms in platelets and vascular tissue, thus blocking a key enzyme involved in VD. Alternatively, platelet activation during heat stress may release substances mediating pathways contributing to VD. We will examine the roles of platelets and vascular COX on reflex VD using systemic interventions (low-dose aspirin and/or platelet inhibitor, clopidogril bisulfate) coupled with a localized examination of NOS- and COX-derived vasodilators. Hypothesis 1: Low-dose aspirin (81 mg) will attenuate reflex cutaneous vasodilation through COX-dependent mechanisms. Hypothesis 2: Specific platelet inhibition with clopidogrel bisulfate will not attenuate reflex cutaneous vasodilation. After screening subjects undergo baseline testing (no oral pharmacologics) incorporating cutaneous microdialysis (MD), whole body heating, and laser Doppler flowmetry. For the testing procedure, four intradermal microdialysis probes will be placed in the skin. Microdialysis sites are assigned drug treatments to serve as to serve as Control, nitric oxide synthase-inhibited (NOS-I), COX-inhibited (COX-I) and NOS and COX inhibited (NOS-I+COX-I). Then subjects enter the double-blind crossover design study with 81 mg of aspirin and/or 75 mg of clopidogrel bisulfate (Plavix ¿). Subjects take each drug for 7 days followed by a 2 week washout before the start of the other drug. Analyses include three-way repeated measures ANOVA. PROC MIXED procedure in SAS.