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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