In this application, we propose a series of experiments designed to Inelp us better understand blood pressure adjustments to exercise in patients with peripheral arterial disease (PAD). Recently obtained pilot data suggests that the pressor response to plantar flexion may be increased in PAD and that reactive oxygen species (ROS) contribute to this enhanced pressor response. In an effort to better understand the role oxidative stress plays in evoking the exercise pressor reflex (EPR) in the absence of chronic arterial disease, we have performed pilot studies in normal humans. These pilot data suggest that ROS contribute to the ischemic potentiation of the EPR. Moreover, chronic cigarette smoldng and acute hyperoxia, both conditions associated with oxidative stress, augment the ischemic accentuation. In this application, we examine the following questions: 1) Are pressor responses to unilateral rhythmic plantar flexion exercise increased in humans with PAD? We hypothesize that pressor responses to exercise will be augmented during exercise by both the "symptomatic" and "asymptomatic" limbs of subjects with unilateral ischemic leg pain with walking (i.e. intermittent claudication). This effect will be greater in the symptomatic limb and this effect will be seen at very low workloads (0.5 kg plantar flexion at 30 contractions per minute), even before symptoms of claudication are noted. 2) Does oxidative stress play a role in evoking the pressor response in PAD? Based on pilot data, we hypothesize that oxidative stress does play an important role in evoking the pressor reflex in PAD. We speculate that an intravenous infusion of the antioxidant, ascorbic acid, will markedly lesson the pressor response to plantar flexion in subjects with intermittent claudication. 3) In the absence of chronic limb ischemia, do ROS contribute to the EPR? We hypothesize that in normal volunteers, oxidative stress leads to ischemic accentuation of the reflex. When handgrip is performed by cigarette smokers or during acute hyperoxia, oxidative stress will be augmented and the ability of the antioxidant ascorbic acid to reduce the pressor response will be enhanced as compared to non-smokers.

Public Health Relevance

In PAD, autonomic reflex and vascular adjustments are understudied and of major clinical significance. PAD is common and lethal. Moreover, it is often a harbinger of other life threatening diseases (coronary and cerebral atherosclerosis). In severe PAD, blood pressure rises dramatically with walking. We postulate that autonomic processes contribute to the augmented pressor response. By better understanding this phenomenon we will better understand how to prevent, treat, and extend the life of those with PAD.

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