Key pointsr Information describing alterations in vascular function during either acute or prolonged normobaric or hypobaric hypoxia is sparse and often confounded by pathology and methodological limitations.r We show that high altitude exposure in lowlanders is associated with impairments in both endothelial and smooth muscle function, and with increased central arterial stiffness; furthermore, in all of these respects, lowlanders' vasculature becomes comparable to that of natives born and raised at altitude.r Changes in endothelial function occur very rapidly in normobaric hypoxia, and partly under the influence of sympathetic nerve activity.r Thus, a lifetime of high-altitude exposure neither attenuates nor intensifies the impairments in vascular function observed with short-term exposure in lowlanders; such impairment and altered structure likely translate into an elevated cardiovascular risk.Abstract Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (ß2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima-media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO 2 -) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3-4 (acute high altitude) and 12-14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders' FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s −1 ; P = 0.001). These changes persisted at days 12-14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (ß19%, P ࣘ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO 2 -increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r = −0.53) and chronic (n = 7, r = −0.69; P ࣘ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n = 11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspired O 2 fraction (F IO 2 ) = 0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure wh...
We examined 1) whether global cerebral blood flow (CBF) would increase across a 6-h bout of normobaric poikilocapnic hypoxia and be mediated by a larger increase in blood flow in the vertebral artery (VA) than in the internal carotid artery (ICA); and 2) whether additional increases in global CBF would be evident following an α1-adrenergic blockade via further dilation of the ICA and VA. In 11 young normotensive individuals, ultrasound measures of ICA and VA flow were obtained in normoxia (baseline) and following 60, 210, and 330 min of hypoxia (FiO2 = 0.11). Ninety minutes prior to final assessment, participants received an α1-adrenoreceptor blocker (prazosin, 1 mg/20 kg body mass) or placebo. Compared with baseline, following 60, 220, and 330 min of hypoxia, global CBF [(ICAFlow + VAFlow) ∗ 2] increased by 160 ± 52 ml/min (+28%; P = 0.05), 134 ± 23 ml/min (+23%; P = 0.02), and 113 ± 51 (+19%; P = 0.27), respectively. Compared with baseline, ICAFlow increased by 23% following 60 min of hypoxia (P = 0.06), after which it progressively declined. The percentage increase in VA flow was consistently larger than ICA flow during hypoxia by ∼20% (P = 0.002). Compared with baseline, ICA and VA diameters increased during hypoxia by ∼9% and ∼12%, respectively (P ≤ 0.05), and were correlated with reductions in SaO2. Flow and diameters were unaltered following α1 blockade (P ≥ 0.10). In conclusion, elevations in global CBF during acute hypoxia are partly mediated via greater increases in VA flow compared with ICA flow; this regional difference was unaltered following α1 blockade, indicating that a heightened sympathetic nerve activity with hypoxia does not constrain further dilation of larger extracranial blood vessels.
Endothelium‐dependent flow‐mediated dilation (FMD) is impaired during exposure to high altitude. Although the time course and mechanism(s) governing this impairment are undefined, hypoxic‐induced elevations in sympathetic outflow may attenuate FMD. We examined the hypothesis that acute exposure to normobaric hypoxia would lead to reductions in FMD that could be reversed via adrenergic blockade. In a placebo‐controlled crossover experiment, brachial FMD, arterial oxygen saturation, blood pressure and heart rate (HR) were assessed in 11 healthy participants (aged 32±7 y) in normobaric normoxia and following 60 min, 210 min and 330 min of normobaric hypoxia (FIO2=0.11). At 210 min, participants ingested an α1‐adrenoreceptor blocker (Prazosin; 1 mg/20 kg body mass) or an identical placebo. Compared to normoxic baseline, FMD was reduced following 60 min, 210, and 330 min of hypoxia by 1.6 ± 0.2% (relative change 28%), 2.5 ± 0.1% and 2.8 ± 0.2% (36%), respectively (P蠄0.003). Following α1‐blockade, FMD and HR at 330 min were 5 ± 2 beats∙min‐1 and 1.8 ± 1.4% (35%) higher compared with the placebo trial (P蠄0.03). In summary, sustained reductions in FMD occur within 60 min of exposure to normobaric hypoxia and are largely mediated via the α1‐adrenoceptor pathway.
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