Cardiopulmonary haemodynamics in Tibetans and Han Chinese during rest and exercise.

During sea-level exercise, blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) in humans without a patent foramen ovale (PFO) is negatively correlated with pulmonary pressure. Yet, it is unknown whether the superior exercise capacity of Tibetans well adapted to living at high altitude is the result of lower pulmonary pressure during exercise in hypoxia, and whether their cardiopulmonary characteristics are significantly different from lowland natives of comparable ancestry (e.g. Han Chinese). We found a 47% PFO prevalence in male Tibetans (n = 19) and Han Chinese (n = 19) participants. In participants without a PFO (n = 10 each group), we measured heart structure and function at rest and peak oxygen uptake ( V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ ), peak power output ( W ̇ p e a k ${{\dot{W}}_{peak}}$ ), pulmonary artery systolic pressure (PASP), blood flow through IPAVA and cardiac output ( Q ̇ T ${{\dot{Q}}_{\mathrm{T}}} $ ) at rest and during recumbent cycle ergometer exercise at 760 Torr (SL) and at 410 Torr (ALT) barometric pressure in a pressure chamber. Tibetans achieved a higher W peak ${W}_{\textit{peak}}$ than Han, and a higher V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ at ALT without differences in heart rate, stroke volume or Q ̇ T ${{\dot{Q}}_{\mathrm{T}}} $ . Blood flow through IPAVA was generally similar between groups. Increases in PASP and total pulmonary resistance at ALT were comparable between the groups. There were no differences in the slopes of PASP plotted as a function of Q ̇ T ${{\dot{Q}}_{\mathrm{T}}} $ during exercise. In those without PFO, our data indicate that the superior aerobic exercise capacity of Tibetans over Han Chinese is independent of cardiopulmonary features and more probably linked to differences in local muscular oxygen extraction. KEY POINTS: Patent foramen ovale (PFO) prevalence was 47% in Tibetans and Han Chinese living at 2 275 m. Subjects with PFO were excluded from exercise studies. Compared to Han Chinese, Tibetans had a higher peak workload with acute compression to sea level barometric pressure (SL) and acute decompression to 5000 m altitude (ALT). Comprehensive cardiac structure and function at rest were not significantly different between Han Chinese and Tibetans. Tibetans and Han had similar blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) during exercise at SL. Peak pulmonary artery systolic pressure (PASP) and total pulmonary resistance were different between SL and ALT, with significantly increased PASP for Han compared to Tibetans at ALT. No differences were observed between groups at acute SL and ALT.

Central and peripheral chemoreflexes in humans with treated hypertension.

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68 ± 5 years; mean ± SD) and 13 normotensives (NT; 65 ± 6 years) performed two modified rebreathing protocols in which the partial pressure of end-tidal carbon dioxide ( P ETC O 2 ${P_{{\rm{ETC}}{{\rm{O}}_2}}}$ ) progressively increased while the partial pressure of end-tidal oxygen was clamped at either 150 mmHg (isoxic hyperoxia; central chemoreflex activation) or 50 mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory ( V ̇ E ${\dot{V}}_{\rm{E}}$ vs. P ETC O 2 ${P_{{\rm{ETC}}{{\rm{O}}_2}}}$  slope) and sympathetic (MSNA vs. P ETC O 2 ${P_{{\rm{ETC}}{{\rm{O}}_2}}}$ slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48 ± 1.33 vs. 1.58 ± 0.42 L min-1  mmHg-1 , P = 0.030: 3.32 ± 1.90 vs. 1.77 ± 0.62 a.u. mmHg-1 , P = 0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for V ̇ E ${\dot{V}}_{\rm{E}}$ (R2  = 0.666, P < 0.0001) and MSNA (R2  = 0.698, P = 0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. KEY POINTS: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented. In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN. We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age-matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities. During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow. These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN.

Sex differences in the sympathetic neurocirculatory responses to chemoreflex activation.

The purpose of this study was to determine whether there are sex differences in the cardiorespiratory and sympathetic neurocirculatory responses to central, peripheral, and combined central and peripheral chemoreflex activation. Ten women (29 ± 6 years, 22.8 ± 2.4 kg/m2 : mean ± SD) and 10 men (30 ± 7 years, 24.8 ± 3.2 kg/m2 ) undertook randomized 5 min breathing trials of: room air (eucapnia), isocapnic hypoxia (10% oxygen (O2 ); peripheral chemoreflex activation), hypercapnic hyperoxia (7% carbon dioxide (CO2 ), 50% O2 ; central chemoreflex activation) and hypercapnic hypoxia (7% CO2 , 10% O2 ; central and peripheral chemoreflex activation). Control trials of isocapnic hyperoxia (peripheral chemoreflex inhibition) and hypocapnic hyperoxia (central and peripheral chemoreflex inhibition) were also included. Muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; finger photoplethysmography) and minute ventilation ( V̇$\dot{\rm{V}}$E ; pneumotachometer) were measured. Total MSNA (P = 1.000 and P = 0.616), MAP (P = 0.265) and V̇$\dot{\rm{V}}$E (P = 0.587 and P = 0.472) were not different in men and women during eucapnia and during isocapnic hypoxia. Women exhibited attenuated increases in V̇$\dot{\rm{V}}$E during hypercapnic hyperoxia (27.3 ± 6.3 vs. 39.5 ± 7.5 l/min, P < 0.0001) and hypercapnic hypoxia (40.9 ± 9.1 vs. 53.8 ± 13.3 l/min, P < 0.0001) compared with men. However, total MSNA responses were augmented in women (hypercapnic hyperoxia 378 ± 215 vs. 258 ± 107%, P = 0.017; hypercapnic hypoxia 607 ± 290 vs. 362 ± 268%, P < 0.0001). No sex differences in total MSNA, MAP or V̇$\dot{\rm{V}}$E were observed during isocapnic hyperoxia and hypocapnic hyperoxia. Our results indicate that young women have augmented sympathetic responses to central chemoreflex activation, which explains the augmented MSNA response to combined central and peripheral chemoreflex activation. KEY POINTS: Sex differences in the control of breathing have been well studied, but whether there are differences in the sympathetic neurocirculatory responses to chemoreflex activation between healthy women and men is incompletely understood. We observed that, compared with young men, young women displayed augmented increases in muscle sympathetic nerve activity during both hypercapnic hyperoxia (central chemoreflex activation) and hypercapnic hypoxia (central and peripheral chemoreflex activation) but had attenuated increases in minute ventilation. In contrast, no sex differences were found in either muscle sympathetic nerve activity or minute ventilation responses to isocapnic hypoxia (peripheral chemoreceptor stimulation). Young women have blunted ventilator, but augmented sympathetic responses, to central (hypercapnic hyperoxia) and combined central and peripheral chemoreflex activation (hypercapnic hypoxia), compared with young men. The possible causative association between the reduced ventilation and heightened sympathetic responses in young women awaits validation.

Effects of hypoxia and hyperoxia on venous capacity and compliance in healthy men and women.

Blood oxygen is an important modulator of arterial function, but its impact on peripheral venous function is incompletely understood. Herein, we sought to determine the effect of hypoxia and hyperoxia on venous capacity and compliance in the lower limb. In 16 healthy individuals (7 women; age: 28.3 ± 7.6 yr, mean ± SD), we assessed peripheral oxygen saturation ([Formula: see text]), the cross-sectional area (CSA) of the great saphenous vein (GSV; Doppler ultrasound), and calf volume (strain-gauge plethysmography) during a standard 60 mmHg thigh cuff inflation-deflation protocol. Separate trials were undertaken during breathing of room air, hypoxia [fraction in inspired oxygen ([Formula: see text]): 0.10], and hyperoxia ([Formula: see text]: 0.50), according to a single-blinded, randomized design. Lower limb pressure-CSA and pressure-volume relationships were modeled using a quadratic regression equation and compliance derived. [Formula: see text] was decreased by hypoxia (83.6 ± 5.6%) and increased by hyperoxia (98.7 ± 0.5%) compared with room air (96.4 ± 1.0%, P < 0.001). Compared with room air (17.0 ± 7.9 mm2), hypoxia decreased GSV CSA (13.4 ± 5.7 mm2, P < 0.001), whereas no change was observed with hyperoxia (17.1 ± 8.7 mm2, P = 0.883). GSV compliance derived from the pressure-CSA relationships was elevated approximately twofold with hyperoxia (-0.0061 ± 0.0046 a.u.) when compared with room air (-0.0029 ± 0.002 a.u., P = 0.027) and hypoxia (-0.0030 ± 0.0032 a.u., P = 0.007). No differences were observed in calf pressure-volume parameters with either hypoxia or hyperoxia (P > 0.05). Our data indicate that GSV capacity is reduced by hypoxia, and that GSV compliance is increased by hyperoxia, thus highlighting the often overlooked role of oxygen in the regulation of venous circulation.

Respiratory alkalinization and posterior cerebral artery dilatation predict acute mountain sickness severity during 10 h normobaric hypoxia.

NEW FINDINGS: What is the central question of this study? The pathophysiology of acute mountain sickness (AMS), involving the respiratory, renal and cerebrovascular systems, remains poorly understood. How do the early adaptations in these systems during a simulated altitude of 5000 m relate to AMS risk? What is the main finding and its importance? The rate of blood alkalosis and cerebral artery dilatation predict AMS severity during the first 10 h of exposure to a simulated altitude of 5000 m. Slow metabolic compensation by the kidneys of respiratory alkalosis attributable to a brisk breathing response together with excessive brain blood vessel dilatation might be involved in early development of AMS. ABSTRACT: The complex pathophysiology of acute mountain sickness (AMS) remains poorly understood and is likely to involve maladaptive responses of the respiratory, renal and cerebrovascular systems to hypoxia. Using stepwise linear regression, we tested the hypothesis that exacerbated respiratory alkalosis, as a result of a brisk ventilatory response, sluggish renal compensation in acute hypoxia and dysregulation of cerebral perfusion predict AMS severity. We assessed the Lake Louise score (LLS, an index of AMS severity), fluid balance, ventilation, venous pH, bicarbonate, sodium and creatinine concentrations, body weight, urinary pH and cerebral blood flow [internal carotid artery (ICA) and vertebral artery (VA) blood flow and diameter], in 27 healthy individuals (13 women) throughout 10 h exposures to normobaric normoxia (fraction of inspired O2 = 0.21) and normobaric hypoxia (fraction of inspired O2 = 0.117, simulated 5000 m) in a randomized, single-blinded manner. In comparison to normoxia, hypoxia increased the LLS, ventilation, venous and urinary pH, and blood flow and diameter in the ICA and VA, while venous concentrations of both bicarbonate and creatinine were decreased (P < 0.001 for all). There were significant correlations between AMS severity and the rates of change in blood pH, sodium concentration and VA diameter and more positive fluid balance (P < 0.05). Stepwise regression found increased blood pH [beta coefficient (ß) = 0.589, P < 0.001] and VA diameter (ß = 0.418, P = 0.008) to be significant predictors of AMS severity in our cohort [F(2, 20) = 16.1, R2  = 0.617, P < 0.001, n = 24], accounting for 62% of the variance in peak LLS. Using classic regression variable selection, our data implicate the degree of respiratory alkalosis and cerebrovascular dilatation in the early stages of AMS development.

AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery.

Cerebral hypoxaemia associated with rapid ascent to high altitude can be life threatening; yet, with proper acclimatization, cerebral function can be maintained well enough for humans to thrive. We investigated adjustments in global and regional cerebral oxygen delivery (DO2) as 21 healthy volunteers rapidly ascended and acclimatized to 5260 m. Ultrasound indices of cerebral blood flow in internal carotid and vertebral arteries were measured at sea level, upon arrival at 5260 m (ALT1; atmospheric pressure 409 mmHg) and after 16 days of acclimatization (ALT16). Cerebral DO2 was calculated as the product of arterial oxygen content and flow in each respective artery and summed to estimate global cerebral blood flow. Vascular resistances were calculated as the quotient of mean arterial pressure and respective flows. Global cerebral blood flow increased by ∼70% upon arrival at ALT1 (P < 0.001) and returned to sea-level values at ALT16 as a result of changes in cerebral vascular resistance. A reciprocal pattern in arterial oxygen content maintained global cerebral DO2 throughout acclimatization, although DO2 to the posterior cerebral circulation was increased by ∼25% at ALT1 (P = 0.032). We conclude that cerebral DO2 is well maintained upon acute exposure and acclimatization to hypoxia, particularly in the posterior and inferior regions of the brain associated with vital homeostatic functions. This tight regulation of cerebral DO2 was achieved through integrated adjustments in local vascular resistances to alter cerebral perfusion during both acute and chronic exposure to hypoxia.

Cerebral oxygenation during the Richalet hypoxia sensitivity test and cycling time-trial performance in severe hypoxia.

BACKGROUND: The Richalet hypoxia sensitivity test (RT), which quantifies the cardiorespiratory response to acute hypoxia during exercise at an intensity corresponding to a heart rate of ~130 bpm in normoxia, can predict susceptibility of altitude sickness. Its ability to predict exercise performance in hypoxia is unknown. OBJECTIVES: Investigate: (1) whether cerebral blood flow (CBF) and cerebral tissue oxygenation (O2Hb; oxygenated hemoglobin, HHb; deoxygenated hemoglobin) responses during RT predict time-trial cycling (TT) performance in severe hypoxia; (2) if subjects with blunted cardiorespiratory responses during RT show greater impairment of TT performance in severe hypoxia. STUDY DESIGN: Thirteen men [27 ± 7 years (mean ± SD), Wmax: 385 ± 30 W] were evaluated with RT and the results related to two 15 km TT, in normoxia and severe hypoxia (FIO2 = 0.11). RESULTS: During RT, mean middle cerebral artery blood velocity (MCAv: index of CBF) was unaltered with hypoxia at rest (p > 0.05), while it was increased during normoxic (+22 ± 12 %, p < 0.05) and hypoxic exercise (+33 ± 17 %, p < 0.05). Resting hypoxia lowered cerebral O2Hb by 2.2 ± 1.2 µmol (p < 0.05 vs. resting normoxia); hypoxic exercise further lowered it to -7.6 ± 3.1 µmol below baseline (p < 0.05). Cerebral HHb, increased by 3.5 ± 1.8 µmol in resting hypoxia (p < 0.05), and further to 8.5 ± 2.9 µmol in hypoxic exercise (p < 0.05). Changes in CBF and cerebral tissue oxygenation during RT did not correlate with TT performance loss (R = 0.4, p > 0.05 and R = 0.5, p > 0.05, respectively), while tissue oxygenation and SaO2 changes during TT did (R = -0.76, p < 0.05). Significant correlations were observed between SaO2, MCAv and HHb during RT (R = -0.77, -0.76 and 0.84 respectively, p < 0.05 in all cases). CONCLUSIONS: CBF and cerebral tissue oxygenation changes during RT do not predict performance impairment in hypoxia. Since the changes in SaO2 and brain HHb during the TT correlated with performance impairment, the hypothesis that brain oxygenation plays a limiting role for global exercise in conditions of severe hypoxia remains to be tested further.

Appetite, Hypoxia, and Acute Mountain Sickness: A 10-Hour Normobaric Hypoxic Chamber Study.

Barclay, Holly, Saptarshi Mukerji, Bengt Kayser, and Jui-Lin Fan. Appetite, hypoxia and acute mountain sickness: A 10-hour normobaric hypoxic chamber study. High Alt Med Biol. 24:329-335, 2023. Background: The effects of hypoxia and acute mountain sickness (AMS) on appetite and food preferences are moot, especially during the early phase of hypoxic exposure. We examined the effects of a 10-hour hypoxic exposure on appetite and food preference. Methods: We assessed appetite (hunger, satisfaction, fullness, perceived appetite, and lost appetite), food preferences (sweet, salty, savory, and fatty), and AMS (Lake Louise score) with questionnaires in 27 healthy individuals (13 women) across 10-hour exposures to normobaric normoxia (fraction of inspired O2 [FiO2]: 0.21) and normobaric hypoxia (FiO2: 0.12, equivalent of 5,000 m) in a randomized, single-blinded manner. Results and Conclusions: Compared with normoxia, hypoxia decreased hunger and appetite (p = 0.040 and <0.001, respectively), which was mediated by a decreased desire for sweet, salty, and fatty foods (p < 0.05 for all). AMS was associated with a decreased desire for sweet (R = -0.438, p = 0.032) and salty foods (R = -0.460, p = 0.024) and greater loss of appetite (R = -0.619, p = 0.018). Our findings suggest that acute hypoxia rapidly suppresses appetite and that AMS development further amplifies anorexia. Clinical Trial Registration Number: ACTRN12618000548235.

AltitudeOmics: effects of 16 days acclimatization to hypobaric hypoxia on muscle oxygen extraction during incremental exercise.

Acute altitude exposure lowers arterial oxygen content ([Formula: see text]) and cardiac output ([Formula: see text]) at peak exercise, whereas O2 extraction from blood to working muscles remains similar. Acclimatization normalizes [Formula: see text] but not peak [Formula: see text] nor peak oxygen consumption (V̇o2peak). To what extent acclimatization impacts muscle O2 extraction remains unresolved. Twenty-one sea-level residents performed an incremental cycling exercise to exhaustion near sea level (SL), in acute (ALT1) and chronic (ALT16) hypoxia (5,260 m). Arterial blood gases, gas exchange at the mouth and oxy- (O2Hb) and deoxyhemoglobin (HHb) of the vastus lateralis were recorded to assess arterial O2 content ([Formula: see text]), [Formula: see text], and V̇o2. The HHb-V̇o2 slope was taken as a surrogate for muscle O2 extraction. During moderate-intensity exercise, HHb-V̇o2 slope increased to a comparable extent at ALT1 (2.13 ± 0.94) and ALT16 (2.03 ± 0.88) compared with SL (1.27 ± 0.12), indicating increased O2 extraction. However, the HHb/[Formula: see text] ratio increased from SL to ALT1 and then tended to go back to SL values at ALT16. During high-intensity exercise, HHb-V̇o2 slope reached a break point beyond which it decreased at SL and ALT1, but not at ALT16. Increased muscle O2 extraction during submaximal exercise was associated with decreased [Formula: see text] in acute hypoxia. The significantly greater muscle O2 extraction during maximal exercise in chronic hypoxia is suggestive of an O2 reserve.NEW & NOTEWORTHY During incremental exercise muscle deoxyhemoglobin (HHb) and oxygen consumption (V̇o2) both increase linearly, and the slope of their relationship is an indirect index of local muscle O2 extraction. The latter was assessed at sea level, in acute and during chronic exposure to 5,260 m. The demonstrated presence of a muscle O2 extraction reserve during chronic exposure is coherent with previous studies indicating both limited muscle oxidative capacity and decrease in motor drive.

Venous capacity and compliance in hypertensive adults: influence of hypoxia and hyperoxia.

In hypertension, the cardiorespiratory responses to peripheral chemoreflex activation (hypoxia) and inactivation (hyperoxia) are reportedly augmented, but the impact on peripheral venous function is unknown. We tested the hypothesis that in hypertensives, both hypoxia and hyperoxia evoke more pronounced changes in lower limb venous capacity and compliance, than in age-matched normotensives. In 10 hypertensive [HTN: 7 women; age: 71.7 ± 3.7 yr, mean blood pressure (BP): 101 ± 10 mmHg, mean ± SD] and 11 normotensive (NT: 6 women; age: 67.7 ± 8.0 yr, mean BP 89 ± 11 mmHg) participants, great saphenous vein cross-sectional area (GSV CSA; Doppler ultrasound) was measured during a standard 60 mmHg thigh cuff inflation-deflation protocol. Separate conditions of room air, hypoxia [fraction of inspired oxygen ([Formula: see text]): 0.10] and hyperoxia ([Formula: see text]: 0.50) were tested. In HTN, GSV CSA was decreased in hypoxia (5.6 ± 3.7 mm2, P = 0.041) compared with room air (7.3 ± 6.9 mm2), whereas no change was observed with hyperoxia (8.0 ± 9.1 mm2, P = 0.988). In NT, no differences in GSV CSA were observed between any condition (P = 0.299). Hypoxia enhanced GSV compliance in HTN (-0.0125 ± 0.0129 vs. -0.0288 ± 0.0090 mm2·100 mm2·mmHg-1, room air vs. hypoxia, respectively; P = 0.004), but it was unchanged in NT (-0.0139 ± 0.0121 vs. -0.0093 ± 0.0066 mm2·100 mm2·mmHg-1, room air vs. hypoxia, respectively; P < 0.541). Venous compliance was unaltered with hyperoxia in both groups (P < 0.05). In summary, compared with NT, hypoxia elicits a decrease in GSV CSA and enhanced GSV compliance in HTN, indicating enhanced venomotor responsiveness to hypoxia.NEW & NOTEWORTHY Hypertension remains a significant global health problem. Although hypertension research and therapies are keenly focused on the heart and arterial circulation, the venous circulation has been neglected comparatively. We determined whether hypoxia, known to cause peripheral chemoreflex activation, evoked more pronounced changes in lower limb venous capacity and compliance in hypertensives (HTN) than in age-matched normotensives (NT). We found that hypoxia reduced venous capacity in the great saphenous vein in HTN and increased its compliance twofold. However, hypoxia did not affect venous function in NT. Our data indicate the venomotor response to hypoxia is enhanced in hypertension, and this may contribute to the hypertensive state.

Effects of acetazolamide on cerebrovascular function and breathing stability at 5050 m.

One of the many actions of the carbonic anhydrase inhibitor, acetazolamide (ACZ), is to accelerate acclimatisation and reduce periodic breathing during sleep. The mechanism(s) by which ACZ may improve breathing stability, especially at high altitude, remain unclear. We tested the hypothesis that acute I.V. ACZ would enhance cerebrovascular reactivity to CO2 at altitude, and thereby lower ventilatory drive and improve breathing stability during wakefulness. We measured arterial blood gases, minute ventilation (˙VE) and middle cerebral artery blood flow velocity (MCAv) before and 30 min following ACZ administration (I.V. 10 mg kg⁻¹) in 12 healthy participants at sea level and following partial acclimatisation to altitude (5050 m).Measures were made at rest and during changes in end-tidal PCO2 and PO2 (isocapnic hypoxia). At sea level, ACZ increased resting MCAv and its reactivity to both hypocapnia and hypercapnia (P < 0.05), and lowered resting VE, arterial O2 saturation (Sa,O2 ) and arterial PO2 (Pa,O2) (P < 0.05); arterial PCO2 (Pa,CO2 ) was unaltered (P > 0.05). At altitude, ACZ also increased resting MCAv and its reactivity to both hypocapnia and hypercapnia (resting MCAv and hypocapnia reactivity to a greater extent than at sea level). Moreover, ACZ at altitude elevated Pa,CO2 and again lowered resting Pa,O2 and Sa,O2 (P <0.05). Although the ˙VE sensitivity to hypercapnia or isocapnic hypoxia was unaltered following ACZ at both sea level and altitude (P > 0.05), breathing stability at altitude was improved (e.g. lower incidence of ventilatory oscillations and variability of tidal volume; P < 0.05). Our data indicate that I.V. ACZ elevates cerebrovascular reactivity and improves breathing stability at altitude, independent of changes in peripheral or central chemoreflex sensitivities. We speculate that Pa,CO2-mediated elevations in cerebral perfusion and an enhanced cerebrovascular reactivity may partly account for the improved breathing stability following ACZ at high altitude.

Effect of drug interventions on cerebral hemodynamics in ischemic stroke patients.

The ischemic penumbra is sensitive to alterations in cerebral perfusion. A myriad of drugs are used in acute ischemic stroke (AIS) management, yet their impact on cerebral hemodynamics is poorly understood. As part of the Cerebral Autoregulation Network led INFOMATAS project (Identifying New Targets for Management and Therapy in Acute Stroke), this paper reviews some of the most common drugs a patient with AIS will come across and their potential influence on cerebral hemodynamics with a particular focus being on cerebral autoregulation (CA). We first discuss how compounds that promote clot lysis and prevent clot formation could potentially impact cerebral hemodynamics, before focusing on how the different classes of antihypertensive drugs can influence cerebral hemodynamics. We discuss the different properties of each drug and their potential impact on cerebral perfusion and CA. With emerging interest in CA status of AIS patients, either during or soon after treatment when timely reperfusion and salvageable tissue is at its most critical, the properties of these pharmacological agents may be relevant for modelling cerebral perfusion accuracy and for setting individualised treatment strategies.

Cerebral autoregulation across the menstrual cycle in eumenorrheic women.

There is emerging evidence that ovarian hormones play a significant role in the lower stroke incidence observed in pre-menopausal women compared with men. However, the role of ovarian hormones in cerebrovascular regulation remains to be elucidated. We examined the blood pressure-cerebral blood flow relationship (cerebral autoregulation) across the menstrual cycle in eumenorrheic women (n = 12; mean ± SD: age, 31 ± 7 years). Participants completed sit-to-stand and Valsalva maneuvers (VM, mouth pressure of 40 mmHg for 15 s) during the early follicular (EF), late follicular (LF), and mid-luteal (ML) menstrual cycle phases, confirmed by serum measurement of progesterone and 17ß-estradiol. Middle cerebral artery blood velocity (MCAv), arterial blood pressure and partial pressure of end-tidal carbon dioxide were measured. Cerebral autoregulation was assessed by transfer function analysis during spontaneous blood pressure oscillations, rate of regulation (RoR) during sit-to-stand maneuvers, and Tieck's autoregulatory index during VM phases II and IV (AI-II and AI-IV, respectively). Resting mean MCAv (MCAvmean ), blood pressure, and cerebral autoregulation were unchanged across the menstrual cycle (all p > 0.12). RoR tended to be different (EF, 0.25 ± 0.06; LF; 0.19 ± 0.04; ML, 0.18 ± 0.12 sec-1 ; p = 0.07) and demonstrated a negative relationship with 17ß-estradiol (R2  = 0.26, p = 0.02). No changes in AI-II (EF, 1.95 ± 1.20; LF, 1.67 ± 0.77 and ML, 1.20 ± 0.55) or AI-IV (EF, 1.35 ± 0.21; LF, 1.27 ± 0.26 and ML, 1.20 ± 0.2) were observed (p = 0.25 and 0.37, respectively). Although, a significant interaction effect (p = 0.02) was observed for the VM MCAvmean response. These data indicate that the menstrual cycle has limited impact on cerebrovascular autoregulation, but individual differences should be considered.

Integrative physiological assessment of cerebral hemodynamics and metabolism in acute ischemic stroke.

Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)-termed cerebral autoregulation (CA)-bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to 'identify novel therapeutic targets for treatment and management in acute ischemic stroke'. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.

Integrative cerebral blood flow regulation in ischemic stroke.

Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.

Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m.

Brain blood flow increases during the first week of living at high altitude. We do not understand completely what causes the increase or how the factors that regulate brain blood flow are affected by the high-altitude environment. Our results show that the balance of oxygen (O(2)) and carbon dioxide (CO(2)) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m). We also show that blood vessels in the brain respond to increases and decreases in CO(2) differently at high altitude compared to sea level, and that this can affect breathing responses as well. These results help us to better understand the regulation of brain blood flow at high altitude and are also relevant to diseases that are accompanied by reductions in the pressure of oxygen in the blood.

Influence of indomethacin on the ventilatory and cerebrovascular responsiveness to hypoxia.

Indomethacin (INDO) has the potential to be a useful tool to explore the influence of cerebral blood flow and its responses to CO(2) on ventilatory control. However, the effect of INDO on the cerebrovascular and ventilatory response to hypoxia remains unclear; therefore, we examined the effect of INDO on ventilatory and cerebrovascular sensitivity to hypoxia and hypercapnia. We measured end-tidal gases, ventilation (V(e)), and middle cerebral artery velocity (MCAv) before and 90 min following INDO (100 mg) in 12 healthy participants at rest and during hyperoxic hypercapnia and isocapnic hypoxia. Following INDO, resting VE and end-tidal gases were unaltered (P > 0.05), whilst MCAv was lowered by 25 ± 19% (P < 0.001). INDO ingestion reduced MCAv-CO(2) reactivity by 46 ± 29% (2.9 ± 0.9 vs. 1.7 ± 0.9 cm s(-1) mmHg(-1); P < 0.001) and enhanced the VE-CO(2) sensitivity by 0.5 ± 0.5 L min(-1) mmHg(-1) (1.9 ± 1.5 vs. 2.3 ± 1.6 L min(-1) mmHg(-1); P < 0.05). No changes were observed in either the MCAv or VE responsiveness to isocapnic hypoxia following INDO ingestion (P > 0.05). These findings indicate that INDO does not alter cerebrovascular and ventilatory responsiveness to hypoxia, indicating a preserved peripheral chemoreflex in response to this pharmacological agent.

Differential Brain and Muscle Tissue Oxygenation Responses to Exercise in Tibetans Compared to Han Chinese.

The Tibetans' better aerobic exercise capacity at altitude remains ill-understood. We tested the hypothesis that Tibetans display better muscle and brain tissue oxygenation during exercise in hypoxia. Using near-infrared spectrometry (NIRS) to provide indices of tissue oxygenation, we measured oxy- and deoxy-hemoglobin ([O2Hb] and [HHb], respectively) responses of the vastus lateralis muscle and the right prefrontal cortex in ten Han Chinese and ten Tibetans during incremental cycling to exhaustion in a pressure-regulated chamber at simulated sea-level (air at 1 atm: normobaric normoxia) and 5,000 m (air at 0.5 atm: hypobaric hypoxia). Hypoxia reduced aerobic capacity by ∼22% in both groups (d = 0.8, p < 0.001 vs. normoxia), while Tibetans consistently outperformed their Han Chinese counterpart by ∼32% in normoxia and hypoxia (d = 1.0, p = 0.008). We found cerebral [O2Hb] was higher in Tibetans at normoxic maximal effort compared Han (p = 0.001), while muscle [O2Hb] was not different (p = 0.240). Hypoxic exercise lowered muscle [O2Hb] in Tibetans by a greater extent than in Han (interaction effect: p < 0.001 vs. normoxic exercise). Muscle [O2Hb] was lower in Tibetans when compared to Han during hypoxic exercise (d = 0.9, p = 0.003), but not during normoxic exercise (d = 0.4, p = 0.240). Muscle [HHb] was not different between the two groups during normoxic and hypoxic exercise (p = 0.778). Compared to Han, our findings revealed a higher brain tissue oxygenation in Tibetans during maximal exercise in normoxia, but lower muscle tissue oxygenation during exercise in hypoxia. This would suggest that the Tibetans privileged oxygenation of the brain at the expense of that of the muscle.