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...

The effect of prior exercise on pulmonary O(2) uptake (Vo(2)(p)), leg blood flow (LBF), and muscle deoxygenation at the onset of heavy-intensity alternate-leg knee-extension (KE) exercise was examined. Seven subjects [27 (5) yr; mean (SD)] performed step transitions (n = 3; 8 min) from passive KE following no warm-up (HVY 1) and heavy-intensity (Delta50%, 8 min; HVY 2) KE exercise. Vo(2)(p) was measured breath-by-breath; LBF was measured by Doppler ultrasound at the femoral artery; and oxy (O(2)Hb)-, deoxy (HHb)-, and total (Hb(tot)) hemoglobin/myoglobin of the vastus lateralis muscle were measured continuously by near-infrared spectroscopy (NIRS; Hamamatsu NIRO-300). Phase 2 Vo(2)(p), LBF, and HHb data were fit with a monoexponential model. The time delay (TD) from exercise onset to an increase in HHb was also determined and an HHb effective time constant (HHb - MRT = TD + tau) was calculated. Prior heavy-intensity exercise resulted in a speeding (P < 0.05) of phase 2 Vo(2)(p) kinetics [HVY 1: 42 s (6); HVY 2: 37 s (8)], with no change in the phase 2 amplitude [HVY 1: 1.43 l/min (0.21); HVY 2: 1.48 l/min (0.21)] or amplitude of the Vo(2)(p) slow component [HVY 1: 0.18 l/min (0.08); HVY 2: 0.18 l/min (0.09)]. O(2)Hb and Hb(tot) were elevated throughout the on-transient following prior heavy-intensity exercise. The tauLBF [HVY 1: 39 s (7); HVY 2: 47 s (21); P = 0.48] and HHb-MRT [HVY 1: 23 s (4); HVY 2: 21 s (7); P = 0.63] were unaffected by prior exercise. However, the increase in HHb [HVY 1: 21 microM (10); HVY 2: 25 microM (10); P < 0.001] and the HHb-to-Vo(2)(p) ratio [(HHb/Vo(2)(p)) HVY 1: 14 microM x l(-1) x min(-1) (6); HVY 2: 17 microM x l(-1) x min(-1) (5); P < 0.05] were greater following prior heavy-intensity exercise. These results suggest that the speeding of phase 2 tauVo(2)(p) was the result of both elevated local O(2) availability and greater O(2) extraction evidenced by the greater HHb amplitude and HHb/Vo(2)(p) ratio following prior heavy-intensity exercise.

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The kinetics of pulmonary O(2) uptake (VO(2p)), limb blood flow (LBF) and deoxygenation (DeltaHHb) of the vastus lateralis (VL) and vastus medialis (VM) muscles during the transition to moderate-intensity knee-extension exercise (MOD) was examined. Seven males (27 +/- 5 years; mean +/- SD) performed repeated step transitions (n = 4) from passive exercise to MOD. Breath by breath VO(2p) femoral artery LBF, and VL and VM muscle DeltaHHb were measured, respectively, by mass spectrometer and volume turbine, Doppler ultrasound and near-infrared spectroscopy. Phase 2 VO(2p), LBF, and HHb data were fit with a mono-exponential model. The time constant (tau) of the VO(2p) and LBF response were not different (tauVO(2p), 24 +/- 6 s; tauLBF, 23 +/- 8 s). The DeltaHHb response did not differ between VL and VM in amplitude (VL 6.97 +/- 4.22 a.u.; VM 7.24 +/- 3.99 a.u.), time delay (DeltaHHb(TD): VL 17 +/- 2 s; VM 15 +/- 1 s), time constant (tauDeltaHHb: VL 11 +/- 6 s; VM 13 +/- 4 s), or effective time constant [tau'DeltaHHb (= DeltaHHb(TD) + tauDeltaHHb): VL 28 +/- 7 s; VM 28 +/- 4 s]. Adjustments in DeltaHHb in VL and VM depict a similar balance of regional O(2) delivery and utilization within the quadriceps muscle group. The tau'DeltaHHb and tauVO(2p) were similar, however, the DeltaHHb displayed an "overshoot" relative to the steady-state levels reflecting a slower alteration of microvascular blood flow (O(2) delivery) relative to O(2) utilization, necessitating a greater reliance on O(2) extraction.

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We investigated if dynamic cerebral pressure-flow relationships in lowlanders are altered at high altitude (HA), differ in HA natives and after return to sea level (SL). Lowlanders were tested at SL (n ¼ 16), arrival to 5,050 m, after 2-week acclimatization (with and without end-tidal PO 2 normalization), and upon SL return. High-altitude natives (n ¼ 16) were tested at 5,050 m. Testing sessions involved resting spontaneous and driven (squat-stand maneuvers at very low (VLF, 0.05 Hz) and low (LF, 0.10 Hz) frequencies) measures to maximize blood pressure (BP) variability and improve assessment of the pressure-flow relationship using transfer function analysis (TFA). Blood flow velocity was assessed in the middle (MCAv) and posterior (PCAv) cerebral arteries. Spontaneous VLF and LF phases were reduced and coherence was elevated with acclimatization to HA (Po0.05), indicating impaired pressureflow coupling. However, when BP was driven, both the frequency-and time-domain metrics were unaltered and comparable with HA natives. Acute mountain sickness was unrelated to TFA metrics. In conclusion, the driven cerebral pressure-flow relationship (in both frequency and time domains) is unaltered at 5,050 m in lowlanders and HA natives. Our findings indicate that spontaneous changes in TFA metrics do not necessarily reflect physiologically important alterations in the capacity of the brain to regulate BP.

Although high‐altitude exposure can lead to neurocognitive impairment, even upon return to sea level, it remains unclear the extent to which brain volume and regional cerebral vascular reactivity (CVR) are altered following high‐altitude exposure. The purpose of this study was to simultaneously determine the effect of 3 weeks at 5050 m on: (1) structural brain alterations; and (2) regional CVR after returning to sea level for 1 week. Healthy human volunteers (n = 6) underwent baseline and follow‐up structural and functional magnetic resonance imaging (MRI) at rest and during a CVR protocol (end‐tidal PCO 2 reduced by −10, −5 and increased by +5, +10, and +15 mmHg from baseline). CVR maps (% mmHg−1) were generated using BOLD MRI and brain volumes were estimated. Following return to sea level, whole‐brain volume and gray matter volume was reduced by 0.4 ± 0.3% (P < 0.01) and 2.6 ± 1.0% (P < 0.001), respectively; white matter was unchanged. Global gray matter CVR and white matter CVR were unchanged following return to sea level, but CVR was selectively increased (P < 0.05) in the brainstem (+30 ± 12%), hippocampus (+12 ± 3%), and thalamus (+10 ± 3%). These changes were the result of improvement and/or reversal of negative CVR to positive CVR in these regions. Three weeks of high‐altitude exposure is reflected in loss of gray matter volume and improvements in negative CVR.

The adjustments of pulmonary oxygen uptake V O2p limb blood flow (LBF) and muscle deoxygenation (ΔHHb) were examined during transitions to moderate-intensity, knee-extension exercise in seven older (OA; 71 ± 7 year) and seven young (YA; 26 ± 3 year) men. YA and OA performed repeated step transitions from an active baseline (3 W; 100 g) to a similar relative intensity of ~80% estimated lactate threshold (θ(L)), and YA also performed the same absolute work rate as the OA (24 W, 800 g). Breath-by-breath V O2p femoral artery LBF (Doppler ultrasound) and muscle HHb (near-infrared spectroscopy) were measured. Phase 2V O2p LBF, and ΔHHb data were fit with a mono-exponential model. τ V O2p was greater in OA (58 ± 21 s) than YA(80%) (31 ± 9 s) and YA(24W) (29 ± 11 s). The increase in LBF per increase in V O2p was not different between groups (5.3-5.8 L min(-1)/L min(-1)); however, the τLBF was greater in OA (44 ± 19 s) than YA(24W) (18 ± 7 s). The overall adjustment in ΔHHb (τ'ΔHHb) was not different between OA and YA, but was faster than τ V O2p in OA. This faster τ'ΔHHb than τ V O2p resulted in an "overshoot" of the normalized ΔHHb/Δ V O2p response relative to the steady state level that was significantly greater in OA compared with YA suggesting that the adjustment of microvascular blood flow is slowed in OA thereby requiring a greater reliance on O(2) extraction during the transition to exercise.