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We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood–brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O2) and following 6 h passive exposure to hypoxia (12% O2). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects developed clinical AMS (AMS+) and were more hypoxaemic relative to subjects without AMS (AMS–). A more marked increase in the venous concentration of the ascorbate radical (A•−), lipid hydroperoxides (LOOH) and increased susceptibility of low-density lipoprotein (LDL) to oxidation was observed during hypoxia in AMS+ (P < 0.05 versus AMS–). Despite a general decline in total nitric oxide (NO) in hypoxia (P < 0.05 versus normoxia), the normoxic baseline plasma and red blood cell (RBC) NO metabolite pool was lower in AMS+ with normalization observed during hypoxia (P < 0.05 versus AMS–). CA was selectively impaired in AMS+ as indicated both by an increase in the low-frequency (0.07–0.20Hz) transfer function gain and decrease in RoR (P < 0.05 versus AMS–). However, there was no evidence for cerebral hyper-perfusion, BBB disruption or neuronal–parenchymal damage as indicated by a lack of change in MCAv, S100β and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

To test the hypothesis that the increased sympathetic tonus elicited by chronic hypoxia is needed to match O2 delivery with O2 demand at the microvascular level eight male subjects were investigated at 4559 m altitude during maximal exercise with and without infusion of ATP (80 μg (kg body mass)−1 min−1) into the right femoral artery. Compared to sea level peak leg vascular conductance was reduced by 39% at altitude. However, the infusion of ATP at altitude did not alter femoral vein blood flow (7.6 ± 1.0 versus 7.9 ± 1.0 l min−1) and femoral arterial oxygen delivery (1.2 ± 0.2 versus 1.3 ± 0.2 l min−1; control and ATP, respectively). Despite the fact that with ATP mean arterial blood pressure decreased (106.9 ± 14.2 versus 83.3 ± 16.0 mmHg, P < 0.05), peak cardiac output remained unchanged. Arterial oxygen extraction fraction was reduced from 85.9 ± 5.3 to 72.0 ± 10.2% (P < 0.05), and the corresponding venous O2 content was increased from 25.5 ± 10.0 to 46.3 ± 18.5 ml l−1 (control and ATP, respectively, P < 0.05). With ATP, leg arterial–venous O2 difference was decreased (P < 0.05) from 139.3 ± 9.0 to 116.9 ± 8.4−1 and leg was 20% lower compared to the control trial (1.1 ± 0.2 versus 0.9 ± 0.1 l min−1) (P= 0.069). In summary, at altitude, some degree of vasoconstriction is needed to match O2 delivery with O2 demand. Peak cardiac output at altitude is not limited by excessive mean arterial pressure. Exercising leg is not limited by restricted vasodilatation in the altitude-acclimatized human.

We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety-Schmidt-determined cerebral blood flow; n = 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n = 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise elicited an uptake of 3.7 +/- 1.3 micromol min(-1) (mean +/-s.e.m.) in the placebo trial and 2.5 +/- 1.0 micromol min(-1) in the glucose trial (P < 0.05 compared to rest, not different across trials). At rest, CSF ammonia was below the detection limit of 2 microm in all subjects, but it increased to 5.3 +/- 1.1 microm following exercise with glucose, and further to 16.1 +/- 3.3 microm after the placebo trial (P < 0.05). Correlations were established between both the cerebral uptake (r2 = 0.87; P < 0.05) and the CSF concentration (r2 = 0.72; P < 0.05) and the arterial ammonia level and, in addition, a weaker correlation (r2 = 0.37; P < 0.05) was established between perceived exertion and CSF ammonia at the end of exercise. The results let us suggest that during prolonged exercise the cerebral uptake and accumulation of ammonia may provoke fatigue, e.g. by affecting neurotransmitter metabolism.

We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood–brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O2) and following 6 h passive exposure to hypoxia (12% O2). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects developed clinical AMS (AMS+) and were more hypoxaemic relative to subjects without AMS (AMS–). A more marked increase in the venous concentration of the ascorbate radical (A•−), lipid hydroperoxides (LOOH) and increased susceptibility of low-density lipoprotein (LDL) to oxidation was observed during hypoxia in AMS+ (P < 0.05 versus AMS–). Despite a general decline in total nitric oxide (NO) in hypoxia (P < 0.05 versus normoxia), the normoxic baseline plasma and red blood cell (RBC) NO metabolite pool was lower in AMS+ with normalization observed during hypoxia (P < 0.05 versus AMS–). CA was selectively impaired in AMS+ as indicated both by an increase in the low-frequency (0.07–0.20Hz) transfer function gain and decrease in RoR (P < 0.05 versus AMS–). However, there was no evidence for cerebral hyper-perfusion, BBB disruption or neuronal–parenchymal damage as indicated by a lack of change in MCAv, S100β and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

To test the hypothesis that the increased sympathetic tonus elicited by chronic hypoxia is needed to match O(2) delivery with O(2) demand at the microvascular level eight male subjects were investigated at 4559 m altitude during maximal exercise with and without infusion of ATP (80 mug (kg body mass)(-1) min(-1)) into the right femoral artery. Compared to sea level peak leg vascular conductance was reduced by 39% at altitude. However, the infusion of ATP at altitude did not alter femoral vein blood flow (7.6 +/- 1.0 versus 7.9 +/- 1.0 l min(-1)) and femoral arterial oxygen delivery (1.2 +/- 0.2 versus 1.3 +/- 0.2 l min(-1); control and ATP, respectively). Despite the fact that with ATP mean arterial blood pressure decreased (106.9 +/- 14.2 versus 83.3 +/- 16.0 mmHg, P0.05), peak cardiac output remained unchanged. Arterial oxygen extraction fraction was reduced from 85.9 +/- 5.3 to 72.0 +/- 10.2% (P0.05), and the corresponding venous O(2) content was increased from 25.5 +/- 10.0 to 46.3 +/- 18.5 ml l(-1) (control and ATP, respectively, P0.05). With ATP, leg arterial-venous O(2) difference was decreased (P0.05) from 139.3 +/- 9.0 to 116.9 +/- 8.4(-1) and leg .VO(2max) was 20% lower compared to the control trial (1.1 +/- 0.2 versus 0.9 +/- 0.1 l min(-1)) (P = 0.069). In summary, at altitude, some degree of vasoconstriction is needed to match O(2) delivery with O(2) demand. Peak cardiac output at altitude is not limited by excessive mean arterial pressure. Exercising leg .VO(2peak) is not limited by restricted vasodilatation in the altitude-acclimatized human.

An altered acid–base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO2 sensitivity at high altitude. Likewise, if [H+] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO2 (termed cerebrovascular CO2 reactivity). However, the effect altered acid–base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO2 remains unclear. We measured ventilation , middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, resting , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O2 and CO2 were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO2 reactivity (2.9 ± 1.1 vs. 4.8 ± 1.4% mmHg−1; P < 0.01) and CO2 sensitivity (3.6 ± 2.3 vs. 5.1 ± 1.7 l min−1 mmHg−1; P < 0.01). Likewise, the hypocapnic MCAv CO2 reactivity was increased at 5050 m (4.2 ± 1.0 vs. 2.0 ± 0.6% mmHg−1; P < 0.01). The hypercapnic MCAv CO2 reactivity correlated with resting pH at high altitude (R2= 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R2= 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO2 sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO2 reactivity and central chemoreflex may be partly attributed to an acid–base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid–base balance in the regulation in CBF and ventilatory control.