Role of reactive oxygen species in mediating peripheral hypoxic vasodilation and sympathoexcitation at high altitude

Abstract High‐altitude acclimatisation increases muscle sympathetic nerve activity (MSNA) via activation of the arterial chemoreflex, pulmonary arterial baroreceptors and resetting of the sympathetic vascular baroreflex. However attempting to silence these mechanisms only partially normalises MSNA, implicating other contributory mechanisms. Increased oxidant production may modulate central sympathetic outflow, while potentially modifying chemosensitivity and vasomotor signalling to the peripheral and pulmonary vasculature. Therefore we tested the hypothesis that blunting oxidative stress would reduce MSNA at high altitude. MSNA (microneurography of the peroneal nerve), continuous arterial pressure (photoplethysmography), vascular tone (duplex ultrasound of the brachial artery), pulmonary artery systolic pressure (PASP, echocardiography) and carotid body tonic activity (1‐min hyperoxia) were measured pre‐ and post‐ascorbic acid infusion (200 mg/min for 15‐min and then 40 mg/min) in healthy lowlanders ( n = 15) after 3–7 days of high‐altitude exposure (3800 m). Ascorbic acid infusion improved the redox environment, determined by an increase in whole cell nuclear factor erythroid 2‐related factor 2 activity ( P = 0.005). Post‐infusion MSNA burst frequency (−2 ± 2 bursts/min, P = 0.007) and incidence (−5 ± 4 bursts/100 heartbeats (HB), P = 0.006) decreased. However the infusion increased mean arterial (9 ± 4 mmHg, P ≤0.001), systolic (11 ± 8 mmHg, P ≤ 0.004) and diastolic pressure (7 ± 4 mmHg, P ≤ 0.001) and total peripheral resistance ( P = 0.013) concomitantly with a reduction in brachial diameter (−0.12 ± 0.14 mm, P = 0.002). Carotid body tonic activity ( P = 0.247) and PASP ( P = 0.365) remained unchanged by ascorbic acid infusion. In conclusion improving the antioxidant environment lowered MSNA at high altitude; however the small reduction is likely a consequence of the increased blood pressure secondary to the blunting of hypoxic vasodilation rather than a direct effect on sympathetic outflow. image Key points High‐altitude acclimatisation increases muscle sympathetic nerve activity (MSNA) from sea level values. Pulmonary artery systolic pressure (PASP), peripheral arterial chemoreflex and high altitude‐induced hypovolaemia are involved in the increase in MSNA; however current evidence indicates additional contributory mechanisms. Hypoxia associated with high altitude results in an increase in the production of reactive oxygen species (ROS), which may be sympathoexcitatory. Therefore we tested the hypothesis that improving the redox environment using an ascorbic acid infusion would lower sympathetic nerve activity. After the infusion, sympathetic nerve activity was reduced alongside an increase in vascular tone and elevation in blood pressure. The reduction in MSNA occurred independently of changes in PASP and chemoreflex activity. Our findings demonstrate that ROS elevates sympathetic nerve activity at high altitude; however this reduction is likely a result of the elevated blood pressure after the blunting of hypoxic vasodilation.