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

Abstract

High altitude‐induced hypoxaemia 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 (4300 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 a 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 than at sea level (P = 0.048). There was no difference in the response to SNP at high altitude (P = 0.860). At sea level, the 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 hypoxaemia (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, a consequence of the magnitude of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high‐altitude sojourns, with important implications for understanding the aetiology of high altitude‐related vascular dysfunction. Key points Vascular dysfunction has been demonstrated in lowlanders at high altitude (>4000 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 4300 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 hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high‐altitude sojourns, with important implications for understanding the aetiology of high altitude‐related changes in endothelial‐mediated vasodilatory function.

Effect of vitamin C infusion on altitude‐related vasodilatory dysfunction

“…The study by Stone et al . (2022) demonstrates impaired endothelial vascular reactivity at high altitudes, the extent of which is determined by the level of hypoxaemia, identifying oxidative stress as a contributing factor to vascular dysfunction. The near reversal of vasodilatory impairment by vitamin C infusion suggests antioxidant supplementation as a means of reducing vascular dysfunction associated with high‐altitude acclimatization, a process that can lead to hypoxia‐related complications.…”

“…This observed difference could be a result of increased oxidative stress on the endothelium, such as seen in metabolic syndrome, although this link has not been investigated in hypobaric hypoxia. As such, in a recent study published in the Journal of Physiology, Stone et al (2022) investigated the mechanism of oxidative stress on endothelial-dependent vasodilatory dysfunction during short-term acclimatization to high altitude. The vascular function of 10 healthy lowlanders in response to ACh, SNP, and ACh + Vitamin C (VitC) was measured at sea level (344 m) and again 4-6 days after rapid ascent to 4300 m elevation via a vehicle in 8 h. Stone et al (2022) quantified vascular function using the gold standard, strain-gauge venous occlusion plethysmography technique to measure arterial forearm blood flow (FBF) following the infusion of endothelial agonists.…”

“…As such, in a recent study published in the Journal of Physiology, Stone et al (2022) investigated the mechanism of oxidative stress on endothelial-dependent vasodilatory dysfunction during short-term acclimatization to high altitude. The vascular function of 10 healthy lowlanders in response to ACh, SNP, and ACh + Vitamin C (VitC) was measured at sea level (344 m) and again 4-6 days after rapid ascent to 4300 m elevation via a vehicle in 8 h. Stone et al (2022) quantified vascular function using the gold standard, strain-gauge venous occlusion plethysmography technique to measure arterial forearm blood flow (FBF) following the infusion of endothelial agonists. To determine the endothelial-dependent and independent vasodilatation, increasing doses of ACh and SNP were infused, respectively.…”

High altitude vascular dysfunction: can we ‘C’ our way to a remedy?

“…By 4–6 days at 4300 m, there was development of decreased hyperaemia mediated by acetylcholine, but not by SNP, and this was abrogated by local intra‐arterial vitamin C infusion in five of the 10 subjects, with little change in three, and a paradoxical fall in two, suggesting a considerable bidirectional range of responses (Figure 3 in Stone et al . 2022). Part of this heterogeneity may be related to the subject's degree of hypoxaemia, because they found a large effect on the degree of individual arterial oxygen desaturation and forearm blood flow increase to acetylcholine, with those most desaturated demonstrating the least increase with acetylcholine and conversely the greatest effect of vitamin C to induce more blood flow.…”

“…Part of this heterogeneity may be related to the subject's degree of hypoxaemia, because they found a large effect on the degree of individual arterial oxygen desaturation and forearm blood flow increase to acetylcholine, with those most desaturated demonstrating the least increase with acetylcholine and conversely the greatest effect of vitamin C to induce more blood flow. In Figure 4 of Stone et al (2022), it would have been interesting to have each subject identified for how vitamin C altered their FMD with acetylcholine. The authors show impaired vascular endothelial cell-mediated hyperaemia by hypoxia after 4-6 days, which is evident even with acute hypoxaemia of half an hour and sustained in subjects studied after 3 weeks in other work by this group.…”