PLATELET INVOLVEMENT IN REFLEX CUTANEOUS VASODILATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 由于非一氧化氮（NO）和NO依赖性机制的减少，人类衰老与高温期间皮肤血管舒张（VD）减弱有关。初步数据表明，用于预防动脉粥样硬化血栓形成疾病的标准阿司匹林治疗严重减弱了中年人皮肤（58 <$3岁）的反射性皮肤血管舒张。 阿司匹林治疗可以抑制血小板和血管组织中的考克斯亚型，从而阻断VD中的一种关键酶。或者，热应激过程中血小板活化可能释放介导导致VD的途径的物质。我们将使用全身干预（低剂量阿司匹林和/或血小板抑制剂，硫酸氢氯吡格雷）结合NOS和COX衍生的血管扩张剂的局部检查来检查血小板和血管考克斯在反射性VD中的作用。 假设1：低剂量阿司匹林（81 mg）将通过COX依赖性机制减弱反射性皮肤血管舒张。 假设2：硫酸氢氯吡格雷的特异性血小板抑制作用不会减弱反射性皮肤血管舒张。 筛选后，受试者接受基线检测（无口服药物），包括皮肤微透析（MD）、全身加热和激光多普勒血流仪。 对于测试程序，将在皮肤中放置四个皮内微透析探针。 微透析部位被分配药物治疗以用作对照、一氧化氮合酶抑制（NOS-I）、COX抑制（COX-I）和NOS和考克斯抑制（NOS-I+COX-I）。 然后，受试者进入双盲交叉设计研究，接受81 mg阿司匹林和/或75 mg硫酸氢氯吡格雷（Plapidogrel）。 受试者服用每种药物7天，然后在开始另一种药物之前进行2周的洗脱。分析包括三因素重复测量ANOVA。 SAS中的PROC MIXED程序。

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.