Oxidative stress contributes to the augmented exercise pressor reflex in peripheral arterial disease patients

Exaggerated blood pressure (BP) responses to dynamic exercise predict cardiovascular mortality in patients with peripheral arterial disease (PAD). However, the underlying mechanisms are unclear and no attempt has been made to attenuate this response using antioxidants. Three physiological studies were conducted in patients with PAD and controls. In Protocol 1, subjects underwent 4 min of low-intensity (0.5-2.0 kg), rhythmic plantar flexion in the supine posture. In Protocol 2, patients with PAD received high-dose ascorbic acid intravenously before exercise. In Protocol 3, involuntary exercise was conducted via electrical stimulation of the tibial nerve. The primary outcome measure was Δ mean arterial pressure (MAP) during the first 20 s of exercise (i.e. the onset of sympathoexcitation by muscle afferents). Compared to controls, patients with PAD had significantly greater ΔMAP during plantar flexion, particularly at 0.5 kg with the most affected leg (11 ± 2 vs. 2 ± 1 mmHg) as well as the least affected leg (7 ± 1 vs. 1 ± 1 mmHg). This augmented response occurred before the onset of claudication pain and was attenuated by ∼50% with ascorbic acid. Electrically evoked exercise also elicited larger haemodynamic changes in patients with PAD compared to controls. Further, the ΔMAP during 0.5 kg plantar flexion inversely correlated with the ankle-brachial index, indicating that patients with more severe resting limb ischaemia have a larger BP response to exercise. The BP response to low-intensity exercise was enhanced in PAD. Chronic limb ischaemia may sensitize muscle afferents and potentiate the BP response to muscle contraction in a dose-dependent manner.