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

Abstract

Key points• Peripheral arterial disease (PAD) is a common and debilitating condition linked with heightened risk of cardiovascular mortality.• Dynamic exercise elicits augmented blood pressure responses in PAD that could put the patient at risk for adverse event but the underlying mechanisms are unknown.• The exercise pressor reflex is comprised of group III and group IV muscle afferents that increase their discharge in response to mechanical and/or chemical stimulation.• In this study, we demonstrate that mechanically sensitive muscle afferents cause augmented reflex elevations in blood pressure during dynamic plantar flexion exercise in PAD. These responses occur prior to claudication pain, are related to disease severity and can be partly reduced by acute antioxidant infusion.Abstract 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 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 MAP 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 MAP 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.

Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease

“…After a 15-min quiet rest period, baseline BPs were obtained via automated oscillometry of the brachial artery (Philips SureSigns Vs3), and a blood sample was obtained for the measurement of thromboxane B 2 (stable marker of thromboxane A2) and 6-keto-PGF1␣ (stable marker of prostacyclin, Penn State Core Endocrine Laboratory, Hershey, PA). The calf of the supine volunteer was supported by cushions to assure a full range of motion (i.e., active plantar flexion), and a custom sandal was affixed to the foot, consistent with previous studies in our laboratory (13,28).…”

“…In recent years, our laboratory has focused on BP control in patients with PAD. Specifically, we found that 1) the BP response to single-leg dynamic plantar flexion exercise was augmented in PAD patients compared with healthy control subjects; 2) the pressor response occurred at very low workloads and before the onset of pain; 3) the pressor response correlated with the anklebrachial index (ABI), suggesting that disease severity plays a role; and 4) intravenous infusion of ascorbic acid lowered the pressor response to exercise in PAD (13,28). To date, the mechanisms for these findings are largely unknown.…”

“…1.0 kg, 1.5 kg, and 2.0 kg) repeated-measures ANOVAs were conducted. The first 20 s of each workload were included in the ANOVA based on our previous findings in PAD patients (28). In healthy control subjects, physiological responses at the 7-kg workload were compared with a paired-samples t-test (i.e., this time point was not used in the ANOVA).…”

Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats

“…This reflex is activated when mechanical and metabolic signals originating within contracting skeletal muscles stimulate thinly myelinated group III and unmyelinated group IV muscle afferents (34,36,44). The exercise pressor reflex is exaggerated in patients with atherosclerotic peripheral artery disease (PAD; 31,39,40) which contributes to the larger increase in blood pressure found during treadmill walking in this patient population compared to that found in aged-matched healthy controls (5, 7). The exercise pressor reflex is also exaggerated in a rat model of simulated PAD in which a femoral artery is ligated ~24-72 hours before the experiment (51).…”

Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease

“…Improving limb blood flow, and possibly oxygen delivery, has the potential to attenuate the rate of development of peripheral muscle fatigue (3). Interestingly, intravenous AO administration also ameliorated the exaggerated exercise pressor reflex during plantar flexion exercise in patients with peripheral artery disease, which was attributed to a reduction in excessive group III/IV afferent stimulation under basal conditions (27). Decreasing the group III/IV afferent signal from the lower limbs has also been documented to extend exercise time to exhaustion in patients with COPD (17).…”