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.