Project 1: The Muscle Reflex: Modes of Engagement and Circulatory Consequences

项目总结/摘要-项目1 在上一个资助期间，我们证明了跖屈运动引起的血压升高 (PFE)与健康受试者相比，外周动脉疾病（PAD）受试者中的此BP 反应是由于在低负荷下观察到的运动加压反射（EPR）增强， 腿部疼痛。我们还证明，静脉注射酮咯酸，一种非- 甾体抗炎药[NSAID（64）]和大剂量静脉内抗坏血酸，一种有效的短期 抗氧化剂（62）。在健康受试者中，这些药物没有效果。因此，花生四烯酸的两种代谢物 氧化应激参与了PAD的EPR。在这次更新中，我们建议进行PAD研究， EPR参与对症状肢体和心脏循环的影响。我们有 开发了新的方法，范例和干预措施，并收集了试点数据，表明我们的 假设是有效的，实验是可行的。 目的1：我们将研究EPR如何影响PAD患者运动腿的血流和氧合 和健康的受试者。 1A. PAD和健康受试者的股动脉和腘动脉对运动的血流反应是否不同？ 1B. PAD和健康受试者对运动的BOLD SI反应是否不同？ 1C.药物干预是否能改善PAD患者对运动的血流和氧合反应？ 1D.腿部血管重建术能改善腿部血流和运动时的氧合反应吗？ 目的2：我们将研究EPR如何影响PAD患者静息腿的血流和氧合 和健康的受试者。 2A. EPR是否增强PAD与健康受试者的静息腿血管收缩？ 2B. PAD和健康受试者的静息腿BOLD SI反应是否不同？ 2C.药物干预是否能改善PAD患者的静息腿血流和氧合？ 2D.下肢血运重建是否能改善PAD患者的静息下肢血流和氧合？ 目的3：我们将研究EPR如何影响PAD患者的冠状动脉血流和左心室功能 和健康的受试者。 3A. PAD和健康人运动时的冠脉血流反应是否不同？ 3B. PAD和健康受试者的左心室运动反应是否不同？ 3C.药物干预是否能改善PAD患者的冠状动脉血流量和左心室功能？ 3D.下肢血运重建是否能改善PAD患者运动时的冠状动脉血流量？ 总之，目标1、2和3使用无创尖端方法了解PAD患者的EPR。

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Over the last funding period, we demonstrated that the rise in blood pressure (BP) with plantar flexion exercise (PFE) is increased in subjects with peripheral arterial disease (PAD) as compared to healthy subjects. This BP response was due to an accentuated exercise pressor reflex (EPR) seen at low workloads, before subjects developed leg pain. We also demonstrated that the EPR is attenuated by both intravenous ketorolac, a non- steroidal anti-inflammatory drug [NSAID (64)] and high dose intravenous ascorbic acid, an effective short-term antioxidant (62). In healthy subjects, these agents had no effect. Thus, both metabolites of arachidonic acid and oxidative stress contribute to the EPR in PAD. In this renewal, we propose PAD studies examining the consequences of EPR engagement on the circulation to the symptomatic limb and the heart. We have developed new methods, paradigms, and interventions and have collected pilot data demonstrating that our hypotheses are valid and the experiments are feasible. AIM 1: We will examine how the EPR affects blood flow and oxygenation in the exercising leg of PAD patients and healthy subjects. 1A. Are femoral and popliteal blood flow responses to exercise different between PAD and healthy subjects? 1B. Are BOLD SI responses to exercise different between PAD and healthy subjects? 1C. Do pharmacological interventions improve blood flow and oxygenation responses to exercise in PAD? 1D. Does leg revascularization improve leg blood flow and oxygenation responses to exercise? AIM 2: We will examine how the EPR affects blood flow and oxygenation in the resting leg of PAD patients and healthy subjects. 2A. Does the EPR enhance resting leg vasoconstriction in PAD vs. healthy subjects? 2B. Are BOLD SI responses in the resting leg different between PAD and healthy subjects? 2C. Do pharmacological interventions improve resting leg blood flow and oxygenation in PAD? 2D. Does leg revascularization improve resting leg blood flow and oxygenation in PAD? AIM 3: We will examine how the EPR affects coronary blood flow and left ventricular function in PAD patients and healthy subjects. 3A. Is the coronary blood flow response to exercise different between PAD and healthy subjects? 3B. Are left ventricular responses to exercise different between PAD and healthy subjects? 3C. Do pharmacological interventions improve coronary blood flow and left ventricular function in PAD? 3D. Does leg revascularization improve coronary blood flow during exercise in PAD? In summary, Aims 1, 2 and 3 use non-invasive cutting-edge methods to understand the EPR in PAD patients.