GLOBAL REACH 2018: intra‐arterial vitamin C improves endothelial‐dependent vasodilatory function in humans at high altitude

Key points Vascular dysfunction has been demonstrated in lowlanders at high-altitude (>4,000 m), however the extent of impairment and the delineation of contributing mechanisms have remained unclear. Using the gold-standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4-6 days after rapid ascent to 4,300 m. The total forearm blood flow response to acetylcholine at high-altitude was decreased by ∼30%. Co-infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by ∼20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourn, with important implications for understanding the etiology of high-altitude related changes in endothelial-mediated vasodilatory function. Abstract High-altitude induced hypoxemia is often associated with peripheral vascular dysfunction; however, the basic mechanism(s) underlying high-altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high-altitude. Ten young healthy lowlanders were tested at sea-level (344 m) and following 4-6 days at high-altitude (4,300 m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain-gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP), and co-infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was ∼30% lower at high-altitude compared to sea-level (P = 0.048). There was no difference in the response to SNP at high-altitude (P = 0.860). At sea-level, co-infusion of ACh+VitC had no influence on the FBF dose response (P = 0.268); however, at high-altitude ACh+VitC resulted in an average increase in the FBF dose response by ∼20% (P = 0.019). At high-altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxemia (R2 = 0.60, P = 0.008 and R2 = 0.63, P = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high-altitude are in part attributable to oxidative stress, consequent of the magnitude of hypoxemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourn, with important implications for understanding the etiology of high-altitude related vascular dysfunction. This article is protected by copyright. All rights reserved.