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1.
J Physiol ; 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409819

RESUMO

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non-invasive normoxic (fraction of inspired oxygen ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) = 0.21) and isobaric hypoxic ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan-Ganz or conductance catheterization to quantify RV performance via pressure-volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12). Median (interquartile range) values for non-invasive V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax , and end-systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular-arterial coupling was maintained during normoxic exercise at 50% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . During submaximal exercise at 50% of hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ , ventricular-arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12 and the associated increase in PA pressures. KEY POINTS: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions. During submaximal exercise, ventricular-arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained. These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure.

2.
J Appl Physiol (1985) ; 135(4): 823-832, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37589059

RESUMO

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.


Assuntos
Hipóxia , Oxigênio , Humanos , Oxigênio/metabolismo , Hipóxia/metabolismo , Exercício Físico/fisiologia , Músculo Quadríceps/fisiologia , Aclimatação/fisiologia , Consumo de Oxigênio/fisiologia , Altitude , Músculo Esquelético/fisiologia
4.
Exp Physiol ; 106(1): 117-125, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363610

RESUMO

NEW FINDINGS: What is the central question of this study? Does the combination of methazolamide and theophylline reduce symptoms of acute mountain sickness (AMS) and improve aerobic performance in acute hypobaric hypoxia? What is the main finding and its importance? The oral combination of methazolamide (100 BID) and theophylline (300 BID) improved arterial oxygen saturation but did not reduce symptoms of AMS and impaired aerobic performance. We do not recommend this combination of drugs for prophylaxis against the acute negative effects of hypobaric hypoxia. ABSTRACT: A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry ( SpO2 ) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (PB  = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (α = 0.05). The drugs improved resting SpO2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance.


Assuntos
Doença da Altitude/tratamento farmacológico , Exercício Físico/fisiologia , Metazolamida/farmacologia , Teofilina/farmacologia , Doença Aguda , Adulto , Altitude , Doença da Altitude/fisiopatologia , Estudos Cross-Over , Método Duplo-Cego , Humanos , Hipóxia/fisiopatologia , Masculino , Saturação de Oxigênio/efeitos dos fármacos
5.
Physiol Rep ; 8(2): e14342, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31960629

RESUMO

The study aim was to compare the predictive validity of the often referenced traditional model of human endurance performance (i.e. oxygen consumption, VO2 , or power at maximal effort, fatigue threshold values, and indices of exercise efficiency) versus measures of skeletal muscle oxidative potential in relation to endurance cycling performance. We hypothesized that skeletal muscle oxidative potential would more completely explain endurance performance than the traditional model, which has never been collectively verified with cycling. Accordingly, we obtained nine measures of VO2 or power at maximal efforts, 20 measures reflective of various fatigue threshold values, 14 indices of cycling efficiency, and near-infrared spectroscopy-derived measures reflecting in vivo skeletal muscle oxidative potential. Forward regression modeling identified variable combinations that best explained 25-km time trial time-to-completion (TTC) across a group of trained male participants (n = 24). The time constant for skeletal muscle oxygen consumption recovery, a validated measure of maximal skeletal muscle respiration, explained 92.7% of TTC variance by itself (Adj R2  = .927, F = 294.2, SEE = 71.2, p < .001). Alternatively, the best complete traditional model of performance, including VO2max (L·min-1 ), %VO2max determined by the ventilatory equivalents method, and cycling economy at 50 W, only explained 76.2% of TTC variance (Adj R2  = .762, F = 25.6, SEE = 128.7, p < .001). These results confirm our hypothesis by demonstrating that maximal rates of skeletal muscle respiration more completely explain cycling endurance performance than even the best combination of traditional variables long postulated to predict human endurance performance.


Assuntos
Treino Aeróbico/métodos , Músculo Esquelético/fisiologia , Consumo de Oxigênio , Resistência Física , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Luz Próxima ao Infravermelho/métodos
6.
Front Physiol ; 10: 1505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31920710

RESUMO

INTRODUCTION: Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Spontaneous baroreflex function can be assessed using continuous recordings of blood pressure. The goal of this study was to compare four methods for BRS quantification [the sequence, Bernardi's (BER), frequency and transfer function methods] to identify the most consistent method across an extreme range of conditions: rest and exercise, in normoxia, hypoxia, hypocapnia, and hypercapnia. METHODS: Using intra-radial artery BP in young healthy participants, BRS was calculated and compared using the four methods in normoxia, acute and chronic hypoxia (terrestrial altitude of 5,260 m) in hypocapnia (hyperventilation), hypercapnia (rebreathing) and during ramp exercise to exhaustion. RESULTS: The sequence and BER methods for BRS estimation showed good agreement during the resting and exercise protocols, whilst the ultra- and very-low frequency bands of the frequency and transfer function methods were more discrepant. Removing respiratory frequency from the blood pressure traces affected primarily the sequence and BER methods and occasionally the frequency and transfer function methods. DISCUSSION/CONCLUSION: The sequence and BER methods contained more respiratory related information than the frequency and transfer function methods, indicating that the former two methods predominantly rely on respiratory effects of BRS. BER method is recommended because it is the easiest to compute and even though it tends to overestimate BRS compared to the sequence method, it is consistent with the other methods, whilst its interquartile range is the smallest.

7.
Med Sci Sports Exerc ; 51(3): 575-581, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30299413

RESUMO

INTRODUCTION: It is well known that supplemental oxygen can increase aerobic power output during high-intensity and/or maximal efforts at moderate altitude, yet the effects on self-selected work rate during lower-intensity, submaximal exercise are unknown. We reasoned that if the degree of arterial oxygen saturation (SaO2) influences teleoanticipatory regulation of power output, supplemental oxygen given at moderate altitude would increase average power output during exercise performed at self-selected work rates corresponding to RPE 9 (very light) and 13 (somewhat hard). METHODS: Twenty-three subjects (17 males, 6 females) completed one familiarization [fraction of inspired O2 (FIO2) = 0.209] and two blinded, experimental trials (FIO2 = 0.209 and FIO2 = 0.267). In each trial, subjects self-regulated their work rate on a cycle ergometer to maintain RPE 9 for 5 min and RPE 13 for 10 min, before performing an incremental step test to exhaustion (25 W·min). Oxygen consumption (V˙O2) and SaO2 via pulse oximetry (SpO2) were continuously monitored. Subjects were asked to guess the experimental condition after each stage of the protocol. RESULTS: Supplemental oxygen increased SpO2 throughout exercise (~4%; P < 0.001) and was associated with greater peak power output (4% ± 4%; P < 0.001) and V˙O2 (5% ± 10%; P = 0.010) during the incremental test, but did not increase average power output selected during exercise at RPE 9 (P = 0.235) or 13 (P = 0.992). Subjects were unable to perceive the difference in FIO2 at any stage (P > 0.14). CONCLUSIONS: Small increases in inspired oxygen concentration at moderate altitude are imperceptible and do not appear to influence selection of submaximal work rates at RPE ≤ 13.


Assuntos
Altitude , Exercício Físico , Consumo de Oxigênio , Oxigênio/administração & dosagem , Adulto , Estudos Cross-Over , Teste de Esforço , Feminino , Humanos , Masculino , Troca Gasosa Pulmonar , Adulto Jovem
8.
Front Physiol ; 9: 767, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977210

RESUMO

Introduction: Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Little is known concerning the adaptive responses of BRS during acclimatization to high altitude at rest and during exercise. Methods: Twenty-one healthy sea-level residents were tested near sea level (SL, 130 m), the 1st (ALT1) and 16th day (ALT16) at 5,260 m using radial artery catheterization. BRS was calculated using the sequence method (direct interpretation of causal link between BP and heartrate). At rest, subjects breathed a hyperoxic mixture (250 mmHg O2, end tidal) to isolate the preponderance of CO2 chemoreceptors. End-tidal CO2 varied from 20 to 50 mmHg to assess peripheral chemoreflex. Rebreathing provoked incremental increase in CO2, increasing BP to assess baroreflex. During incremental cycling exercise to exhaustion, subjects breathed room air. Results: Resting BRS decreased in ALT1 which was exacerbated in ALT16. This decrease in ALT1 was reversible upon additional inspired CO2, but not in ALT16. BRS decrease during exercise was greater and occurred at lower workloads in ALT1 compared to SL. At ALT16, this decrease returned toward SL values. Discussion/Conclusion: This study is the first to report attenuated BRS in acute hypoxia, exacerbated in chronic hypoxia. In ALT1, hypocapnia triggered BRS reduction whilst in ALT16 resetting of chemoreceptor triggered BRS reduction. The exercise BRS resetting was impaired in ALT1 but normalized in ALT16. These BRS decreases indicate decreased control of BP and may explain deteriorations of cardiovascular status during exposure to high altitude.

9.
J Biol Chem ; 293(18): 6659-6671, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29540485

RESUMO

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity in vivo Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.


Assuntos
Aclimatação , Doença da Altitude/metabolismo , Doença da Altitude/fisiopatologia , Altitude , Metabolismo Energético/fisiologia , Metaboloma , Músculo Esquelético/metabolismo , Proteômica , Aminoácidos/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Ácidos Graxos/metabolismo , Feminino , Glicólise , Voluntários Saudáveis , Humanos , Masculino , Mitocôndrias Musculares/metabolismo , Proteínas Musculares/metabolismo , Oxirredução , Via de Pentose Fosfato , Fosforilação , Proteólise , Nucleotídeos de Purina/metabolismo , Distribuição Aleatória , Estresse Fisiológico , Adulto Jovem
11.
Physiol Rep ; 5(4)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28242827

RESUMO

Cerebral autoregulation (CA) is thought to maintain relatively constant cerebral blood flow (CBF) across normal blood pressures. To determine if postural changes alter CA, we measured cerebral blood flow velocity (CBFv) in the middle cerebral arteries, mean arterial blood pressure (MABP), cardiac output (Q), and end-tidal carbon dioxide (PETCO2) in 18 healthy individuals (11 female and seven male; 26 ± 9 years) during repeated periods of supine and seated rest. Multiple regression was used to evaluate the influence of PETCO2, MABP, Q, and hydrostatic pressure on CBFv. Static CA was assessed by evaluating absolute changes in steady-state CBFv. Dynamic CA was assessed by transfer function analysis of the CBFv response to spontaneous oscillations in MABP In the seated versus supine posture, MABP (67.2 ± 7.2 vs. 84.2 ± 12.1 mmHg; P < 0.001), CBFv (55.2 ± 9.1 vs. 63.6 ± 10.6 cm/sec; P < 0.001) and PETCO2 (29.1 ± 2.6 vs. 30.9 ± 2.3 mmHg; P < 0.001) were reduced. Changes in CBFv were not explained by variance in PETCO2, MABP, Q, or hydrostatic pressure. A reduction in MABP to CBFv transfer function gain while seated (P < 0.01) was explained by changes in the power spectrum of MABP, not CBFv. Our findings suggest that changes in steady-state cerebral hemodynamics between postures do not appear to have a large functional consequence on the dynamic regulation of CBF.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular/fisiologia , Homeostase/fisiologia , Postura/fisiologia , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Feminino , Humanos , Masculino , Adulto Jovem
12.
Exp Physiol ; 102(3): 384, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28247478
13.
Nat Commun ; 8: 14108, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28169986

RESUMO

Faster acclimatization to high altitude upon re-ascent is seen in humans; however, the molecular basis for this enhanced adaptive response is unknown. We report that in healthy lowlanders, plasma adenosine levels are rapidly induced by initial ascent to high altitude and achieved even higher levels upon re-ascent, a feature that is positively associated with quicker acclimatization. Erythrocyte equilibrative nucleoside transporter 1 (eENT1) levels are reduced in humans at high altitude and in mice under hypoxia. eENT1 deletion allows rapid accumulation of plasma adenosine to counteract hypoxic tissue damage in mice. Adenosine signalling via erythrocyte ADORA2B induces PKA phosphorylation, ubiquitination and proteasomal degradation of eENT1. Reduced eENT1 resulting from initial hypoxia is maintained upon re-ascent in humans or re-exposure to hypoxia in mice and accounts for erythrocyte hypoxic memory and faster acclimatization. Our findings suggest that targeting identified purinergic-signalling network would enhance the hypoxia adenosine response to counteract hypoxia-induced maladaptation.


Assuntos
Aclimatação/fisiologia , Adenosina/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Eritrócitos/fisiologia , Hipóxia/fisiopatologia , Receptor A2B de Adenosina/metabolismo , 5'-Nucleotidase/sangue , 5'-Nucleotidase/metabolismo , Adenosina/sangue , Adulto , Altitude , Doença da Altitude/sangue , Doença da Altitude/fisiopatologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/sangue , Transportador Equilibrativo 1 de Nucleosídeo/genética , Feminino , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Voluntários Saudáveis , Humanos , Hipóxia/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigênio/metabolismo , Fosforilação , Receptor A2B de Adenosina/genética , Transdução de Sinais/fisiologia , Ubiquitinação , Adulto Jovem
14.
J Proteome Res ; 15(10): 3883-3895, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27646145

RESUMO

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.


Assuntos
Adaptação Fisiológica , Doença da Altitude/metabolismo , Eritrócitos/metabolismo , Aclimatação/fisiologia , Adulto , Altitude , Doença da Altitude/fisiopatologia , Arginina/metabolismo , Glutationa/metabolismo , Glicólise , Voluntários Saudáveis , Humanos , Via de Pentose Fosfato , Purinas/metabolismo , Enxofre/metabolismo , Fatores de Tempo , Adulto Jovem
15.
Circulation ; 134(5): 405-21, 2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27482003

RESUMO

BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.


Assuntos
Proteínas Quinases Ativadas por AMP/sangue , Adaptação Fisiológica/fisiologia , Doença da Altitude/sangue , Eritrócitos/metabolismo , Receptor A2B de Adenosina/sangue , 2,3-Difosfoglicerato/sangue , 5'-Nucleotidase/sangue , 5'-Nucleotidase/deficiência , Lesão Pulmonar Aguda/fisiopatologia , Adenosina/sangue , Adulto , Doença da Altitude/enzimologia , Doença da Altitude/fisiopatologia , Animais , Bisfosfoglicerato Mutase/sangue , Ativação Enzimática , Proteínas Ligadas por GPI/sangue , Humanos , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigênio/sangue , Fosforilação , Processamento de Proteína Pós-Traducional
16.
Nat Commun ; 7: 12086, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27417539

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2 release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O2 release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O2 delivery and thus new therapeutic opportunities to counteract tissue hypoxia.


Assuntos
Doença da Altitude/metabolismo , Eritrócitos/metabolismo , Lisofosfolipídeos/sangue , Oxigênio/sangue , Esfingosina/análogos & derivados , 2,3-Difosfoglicerato/metabolismo , Adaptação Fisiológica , Adulto , Animais , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Glicólise , Humanos , Hipóxia/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Oxigênio/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/sangue , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Esfingosina/sangue , Esfingosina/metabolismo
17.
Exp Physiol ; 101(10): 1276-1284, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27435029

RESUMO

NEW FINDINGS: What is the central question of this study? Acute hypoxia reduces dynamic cerebral autoregulation (dCA); however, it is unclear what level of hypoxia is necessary to exert this effect. We sought to investigate whether dCA would be reduced during progressive periods of normobaric hypoxia using a duplex Doppler ultrasound technique to evaluate the volumetric blood flow. What is the main finding and its importance? We showed that dCA decreased linearly as inspired O2 decreased from 21 to 12%. Additionally, symptoms of acute mountain sickness were related to changes in dCA. Our results may provide a sensitive and clinically relevant test to evaluate the risk of acute mountain sickness. Cerebral blood flow is maintained at relatively constant levels over a wide range of perfusion pressures via cerebral autoregulation (CA). Although acute hypoxia reduces dynamic CA, it is unclear what level of hypoxia is necessary to exert this effect. We evaluated dynamic CA during progressive normobaric hypoxia (∼1 h at each of 21, 18, 15 and 12% O2 ) using duplex ultrasonography to measure volumetric changes in common carotid artery blood flow of 11 healthy young men. Dynamic CA was evaluated by the thigh-cuff method and represented as the rate of regulation of vascular conductance. On a separate occasion, symptoms of acute mountain sickness were evaluated during 6 h of prolonged hypoxia (fractional inspired O2 of 14.1%) using the Lake Louise Questionnaire. Repeated-measures ANOVA with linear trend analysis indicated that dynamic CA decreased progressively as fractional inspired O2 was reduced (P < 0.001). Spearman rank order analysis revealed that symptoms of acute mountain sickness were related to changes in the rate of regulation of vascular conductance from 21 to 15% (r = -0.869, P = 0.006) and from 21 to 12% O2 (r = -0.648, P = 0.040), respectively. These results suggest that dynamic CA worsens with progressive hypoxia and that reductions in dynamic CA during moderate to severe hypoxia (<15% O2 ) may be related to the severity of acute mountain sickness.


Assuntos
Encéfalo/fisiopatologia , Homeostase/fisiologia , Hipóxia/fisiopatologia , Doença Aguda , Adulto , Doença da Altitude/metabolismo , Doença da Altitude/fisiopatologia , Encéfalo/metabolismo , Artérias Carótidas/metabolismo , Artérias Carótidas/fisiopatologia , Circulação Cerebrovascular/fisiologia , Humanos , Hipóxia/metabolismo , Oxigênio/metabolismo , Adulto Jovem
18.
Adv Exp Med Biol ; 876: 95-100, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26782200

RESUMO

We investigated the relation between blood pressure and cerebral oxygenation (COX) immediately after exercise in ten healthy males. Subjects completed an exercise and recovery protocol while breathing either 21% (normoxia) or 14.1% (hypoxia) O2 in a randomized order. Each exercise session included four sets of cycling (30 min/set, 15 min rest) at 50% of altitude-adjusted peak oxygen uptake, followed by 60 min of recovery. After exercise, mean arterial pressure (MAP; 87±1 vs. 84±1 mmHg, average values across the recovery period) and COX (68±1% vs. 58±1%) were lower in hypoxia compared to normoxia (P<0.001). Changes in MAP and COX were correlated during the recovery period in hypoxia (r=0.568, P<0.001) but not during normoxia (r=0.028, not significant). These results demonstrate that reductions in blood pressure following exercise in hypoxia are (1) more pronounced than in normoxia, and (2) associated with reductions in COX. Together, these results suggest an impairment in cerebral autoregulation as COX followed changes in MAP more passively in hypoxia than in normoxia. These findings could help explain the increased risk for postexercise syncope at high altitude.


Assuntos
Pressão Arterial/fisiologia , Encéfalo/metabolismo , Exercício Físico/fisiologia , Hipóxia/metabolismo , Oxigênio/metabolismo , Adulto , Altitude , Humanos , Masculino , Síncope/etiologia
19.
J Appl Physiol (1985) ; 120(2): 251-62, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26494441

RESUMO

The pathophysiology of acute mountain sickness and high-altitude cerebral edema, the cerebral forms of high-altitude illness, remain uncertain and controversial. Persistently elevated or pathological fluctuations in intracranial pressure are thought to cause symptoms similar to those reported by individuals suffering cerebral forms of high-altitude illness. This review first focuses on the basic physiology of the craniospinal system, including a detailed discussion of the long-term and dynamic regulation of intracranial pressure. Thereafter, we critically examine the available literature, based primarily on invasive pressure monitoring, that suggests intracranial pressure is acutely elevated at altitude due to brain swelling and/or elevated sagittal sinus pressure, but normalizes over time. We hypothesize that fluctuations in intracranial pressure occur around a slightly elevated or normal mean intracranial pressure, in conjunction with oscillations in arterial Po2 and arterial blood pressure. Then these modest fluctuations in intracranial pressure, in concert with direct vascular stretch due to dilatation and/or increased blood pressure transmission, activate the trigeminal vascular system and cause symptoms of acute mountain sickness. Elevated brain water (vasogenic edema) may be due to breakdown of the blood-brain barrier. However, new information suggests cerebral spinal fluid flux into the brain may be an important factor. Regardless of the source (or mechanisms responsible) for the excess brain water, brain swelling occurs, and a "tight fit" brain would be a major risk factor to produce symptoms; activities that produce large changes in brain volume and cause fluctuations in blood pressure are likely contributing factors.


Assuntos
Doença da Altitude/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Hipóxia/fisiopatologia , Altitude , Animais , Humanos , Pressão Intracraniana/fisiologia
20.
J Appl Physiol (1985) ; 118(9): 1100-12, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25678698

RESUMO

A patent foramen ovale (PFO), present in ∼40% of the general population, is a potential source of right-to-left shunt that can impair pulmonary gas exchange efficiency [i.e., increase the alveolar-to-arterial Po2 difference (A-aDO2)]. Prior studies investigating human acclimatization to high-altitude with A-aDO2 as a key parameter have not investigated differences between subjects with (PFO+) or without a PFO (PFO-). We hypothesized that in PFO+ subjects A-aDO2 would not improve (i.e., decrease) after acclimatization to high altitude compared with PFO- subjects. Twenty-one (11 PFO+) healthy sea-level residents were studied at rest and during cycle ergometer exercise at the highest iso-workload achieved at sea level (SL), after acute transport to 5,260 m (ALT1), and again at 5,260 m after 16 days of high-altitude acclimatization (ALT16). In contrast to PFO- subjects, PFO+ subjects had 1) no improvement in A-aDO2 at rest and during exercise at ALT16 compared with ALT1, 2) no significant increase in resting alveolar ventilation, or alveolar Po2, at ALT16 compared with ALT1, and consequently had 3) an increased arterial Pco2 and decreased arterial Po2 and arterial O2 saturation at rest at ALT16. Furthermore, PFO+ subjects had an increased incidence of acute mountain sickness (AMS) at ALT1 concomitant with significantly lower peripheral O2 saturation (SpO2). These data suggest that PFO+ subjects have increased susceptibility to AMS when not taking prophylactic treatments, that right-to-left shunt through a PFO impairs pulmonary gas exchange efficiency even after acclimatization to high altitude, and that PFO+ subjects have blunted ventilatory acclimatization after 16 days at altitude compared with PFO- subjects.


Assuntos
Aclimatação/fisiologia , Forame Oval Patente/fisiopatologia , Troca Gasosa Pulmonar/fisiologia , Adulto , Altitude , Doença da Altitude/fisiopatologia , Gasometria/métodos , Dióxido de Carbono/metabolismo , Exercício Físico/fisiologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Descanso/fisiologia , Adulto Jovem
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