Cerebral blood flow regulation in hypobaric hypoxia: role of haemoconcentration.

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty-three healthy lowlanders (12 females) completed two identical 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500 m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96 h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1 h (P = 0.001) but similar at all later time points (all P > 0.199). Haemoglobin concentration was higher in HH than NX from 12 h to 96 h (all P < 0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2 g·dl-1 (P < 0.001), it did not increase CBF (974 ± 282 to 872 ± 200 ml·min-1; P = 0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO2. KEY POINTS: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes. We investigated whether hypoxia-induced haemoconcentration contributes to the normalization of CBF during extended hypoxia. Following 4 days of hypobaric hypoxic exposure (corresponding to 3500 m altitude), we measured CBF before and after abolishing hypoxia-induced haemoconcentration by hypervolaemic haemodilution. Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia. Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia.

Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m.

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ∼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline.NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Selected and shared hematological responses to apnea in elite human free divers and northern elephant seals (Mirounga angustirostris).

Despite elite human free divers achieving incredible feats in competitive free diving, there has yet to be a study that compares consummate divers, (i.e. northern elephant seals) to highly conditioned free divers (i.e., elite competitive free-diving humans). Herein, we compare these two diving models and suggest that hematological traits detected in seals reflect species-specific specializations, while hematological traits shared between the two species are fundamental mammalian characteristics. Arterial blood samples were analyzed in elite human free divers (n = 14) during a single, maximal volitional apnea and in juvenile northern elephant seals (n = 3) during rest-associated apnea. Humans and elephant seals had comparable apnea durations (∼6.5 min) and end-apneic arterial Po2 [humans: 40.4 ± 3.0 mmHg (means ± SE); seals: 27.1 ± 5.9 mmHg; P = 0.2]. Despite similar increases in arterial Pco2 (humans: 33 ± 5%; seals: 16.3 ± 5%; P = 0.2), only humans experienced reductions in pH from baseline (humans: 7.45 ± 0.01; seals: 7.39 ± 0.02) to end apnea (humans: 7.37 ± 0.01; seals: 7.38 ± 0.02; P < 0.0001). Hemoglobin P50 was greater in humans compared to elephant seals (29.9 ± 1.5 and 28.7 ± 0.6 mmHg, respectively; P = 0.046). Elephant seals overall had higher carboxyhemoglobin (COHb) levels (5.9 ± 2.6%) compared to humans (0.8 ± 1.2%; P < 0.0001); however, following apnea, COHb was reduced in seals (baseline: 6.1 ± 0.3%; end apnea: 5.6 ± 0.3%) and was slightly elevated in humans (baseline: 0.7 ± 0.1%; end apnea: 0.9 ± 0.1%; P < 0.0002, both comparisons). Our data indicate that during static apnea, seals have reduced hemoglobin P50, greater pH buffering, and increased COHb levels. The differences in hemoglobin P50 are likely due to the differences in the physiological environment between the two species during apnea, whereas enhanced pH buffering and higher COHb may represent traits selected for in elephant seals.NEW & NOTEWORTHY This study uses similar methods and protocols in elite human free divers and northern elephant seals. Using highly conditioned divers (elite free-diving humans) and highly adapted divers (northern elephant seals), we explored which hematological traits are fundamentally mammalian and which may have been selected for. We found differences in P50, which may be due to different physiological environments between species, while elevated pH buffering and carbon monoxide levels might have been selected for in seals.

Global and country-level estimates of human population at high altitude.

Estimates of the global population of humans living at high altitude vary widely, and such data at the country level are unavailable. Herein, we use a geographic information system (GIS)-based approach to quantify human population at 500-m elevation intervals for each country. Based on georeferenced data for population (LandScan Global 2019) and elevation (Global Multiresolution Terrain Elevation Data), 500.3 million humans live at ≥1,500 m, 81.6 million at ≥2,500 m, and 14.4 million at ≥3,500 m. Ethiopia has the largest absolute population at ≥1,500 m and ≥2,500 m, while China has the greatest at ≥3,500 m. Lesotho has the greatest percentage of its population above 1,500 m, while Bolivia has the greatest at ≥2,500 m and ≥3,500 m. High altitude presents a myriad of environmental stresses that provoke physiological responses and adaptation, and consequently impact disease prevalence and severity. While the majority of high-altitude physiology research is based upon lowlanders from western, educated, industrialized, rich, and democratic countries ascending to high altitude, the global population distribution of high-altitude residents encourages an increased emphasis on understanding high-altitude physiology, adaptation, epidemiology, and public health in the ∼500 million permanent high-altitude residents.

Creating your own line: reflections from early career scientists.

The changing landscape of academia can be difficult to navigate for anyone at any point throughout their career. One thing is certainly clear: effective mentorship is key to ensuring success, fueling scientific curiosity, and creating a sense of community. This article is a collection of personal reflections and stories, offering advice directed to aspiring and junior graduate trainees; it is written by Ph.D. students, postdoctoral researchers, early-stage assistant professors, and life-long educators. The objective of this article is to inform, empower, and inspire the next generation of physiologists.NEW & NOTEWORTHY This article is a collection of personal reflections and stories, offering advice directed to aspiring and junior graduate trainees that is written by Ph.D. students, postdoctoral researchers, early-stage assistant professors, and life-long educators. The objective of this article is to inform, empower, and inspire the next generation of physiologists.

Mountains of research: Where and whom high-altitude physiology has overlooked.

High altitude is a natural setting in which to study human acclimatization and adaptation. Here, I identify where and in whom high-altitude physiology research has occurred. There has been a mismatch between countries with large high-altitude populations vs. where high-altitude research has been conducted. From 1970 to 2020, 83% of high-altitude physiology research took place in just seven countries: Nepal, China, USA, Peru, India, Bolivia and Italy. Collectively, these countries account for only 35% of the global population living above 2500 m. Furthermore, high-altitude physiology research has predominantly studied low-altitude residents visiting high altitude and female participants are under-represented. Accordingly, the included populations are not necessarily a proportional representation of high-altitude residents. Here, I discuss how this influences our understanding of high-altitude adaptation. Finally, I highlight past initiatives to increase diversity in high-altitude research. By identifying the broad gaps in high-altitude physiology research, I propose exciting, inclusive opportunities to study human high-altitude physiology.

Body mass and growth rates in captive chimpanzees (Pan troglodytes) cared for in African wildlife sanctuaries, zoological institutions, and research facilities.

Captive chimpanzees (Pan troglodytes) mature earlier in body mass and have a greater growth rate compared to wild individuals. However, relatively little is known about how growth parameters compare between chimpanzees living in different captive environments. To investigate, body mass was measured in 298 African sanctuary chimpanzees and was acquired from 1030 zoological and 442 research chimpanzees, using data repositories. An analysis of covariance, adjusting for age, was performed to assess same-sex body mass differences between adult sanctuary, zoological, and research populations. Piecewise linear regression was performed to estimate sex-specific growth rates and the age at maturation, which were compared between sexes and across populations using extra-sum-of-squares F tests. Adult body mass was greater in the zoological and resarch populations compared to the sanctuary chimpanzees, in both sexes. Male and female sanctuary chimpanzees were estimated to have a slower rate of growth compared with their zoological and research counterparts. Additionally, male sanctuary chimpanzees were estimated to have an older age at maturation for body mass compared with zoological and research males, whereas the age at maturation was similar across female populations. For both the zoological and research populations, the estimated growth rate was greater in males compared to females. Together, these data contribute to current understanding of growth and maturation in this species and suggest marked differences between the growth patterns of chimpanzees living in different captive environments.

GLOBAL REACH 2018: intra-arterial vitamin C improves endothelial-dependent vasodilatory function in humans at high altitude.

High altitude-induced hypoxaemia is often associated with peripheral vascular dysfunction. However, the basic mechanism(s) underlying high-altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high altitude. Ten young healthy lowlanders were tested at sea level (344 m) and following 4-6 days at high altitude (4300 m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain-gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP) and a co-infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was ∼30% lower at high altitude than at sea level (P = 0.048). There was no difference in the response to SNP at high altitude (P = 0.860). At sea level, the co-infusion of ACh+VitC had no influence on the FBF dose response (P = 0.268); however, at high altitude ACh+VitC resulted in an average increase in the FBF dose response by ∼20% (P = 0.019). At high altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxaemia (R2 = 0.60, P = 0.008 and R2 = 0.63, P = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high altitude are in part attributable to oxidative stress, a consequence of the magnitude of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourns, with important implications for understanding the aetiology of high altitude-related vascular dysfunction. KEY POINTS: Vascular dysfunction has been demonstrated in lowlanders at high altitude (>4000 m). However, the extent of impairment and the delineation of contributing mechanisms have remained unclear. Using the gold-standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4-6 days after rapid ascent to 4300 m. The total forearm blood flow response to acetylcholine at high altitude was decreased by ∼30%. Co-infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by ∼20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourns, with important implications for understanding the aetiology of high altitude-related changes in endothelial-mediated vasodilatory function.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO2- exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO2- by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO2 ; P = 0.044) shifted trans-cerebral NO2- exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO2- release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO2 test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO2 stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO2 stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO2 test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase inhibitor NG -monomethyl-l-arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady-state CO2 test; however, cerebral shear-mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG -monomethyl-l-arginine. NO is not obligatory for cerebrovascular reactivity to CO2 , but is a key contributor to cerebral shear-mediated dilatation.

Brachial artery responses to acute hypercapnia: The roles of shear stress and adrenergic tone.

NEW FINDINGS: What is the central question of this study? What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia? What is the main finding and its importance? In healthy young adults, shear-mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α1-adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. ABSTRACT: We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α1-adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α1-adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end-tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end-tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α1-adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α1-adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear-mediated vasodilatation in the BA.

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3- ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in PaCO2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3- ) to acutely elevate arterial pH and [HCO3- ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of PaCO2 , indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between PaCO2 and H+ /pH following NaHCO3- infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3- infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3- independent of PaCO2 levels. ABSTRACT: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial PCO2 ( PaCO2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in PaCO2 or intravascular bicarbonate ([HCO3- ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3- ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO3- ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L-1 ; P < 0.001). Absolute CBF was not different at each stage of CO2 reactivity (P = 0.629) following NaHCO3- , irrespective of a higher pH (P < 0.001) at each matched stage of PaCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg PaCO2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg PaCO2 ; P = 0.151) reactivity to PaCO2 were altered pre- to post-NaHCO3- . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3- , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between PaCO2 and arterial H+ /pH consequent to NaHCO3- . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3- during isocapnic breathing providing support for a direct influence of HCO3- on cerebrovascular tone independent of PaCO2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by PaCO2 rather than arterial pH.

Alterations in arterial CO2 rather than pH affect the kinetics of neurovascular coupling in humans.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. ABSTRACT: Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial PCO2 ( PaCO2 ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, PaCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO3- ] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27-38% with -10 mmHg PaCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO3 (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.

The 2018 Global Research Expedition on Altitude Related Chronic Health (Global REACH) to Cerro de Pasco, Peru: an Experimental Overview.

NEW FINDINGS: What is the central question of this study? Herein, a methodological overview of our research team's (Global REACH) latest high altitude research expedition to Peru is provided. What is the main finding and its importance? The experimental objectives, expedition organization, measurements and key cohort data are discussed. The select data presented in this manuscript demonstrate the haematological differences between lowlanders and Andeans with and without excessive erythrocytosis. The data also demonstrate that exercise capacity was similar between study groups at high altitude. The forthcoming findings from our research expedition will contribute to our understanding of lowlander and indigenous highlander high altitude adaptation. ABSTRACT: In 2016, the international research team Global Research Expedition on Altitude Related Chronic Health (Global REACH) was established and executed a high altitude research expedition to Nepal. The team consists of ∼45 students, principal investigators and physicians with the common objective of conducting experiments focused on high altitude adaptation in lowlanders and in highlanders with lifelong exposure to high altitude. In 2018, Global REACH travelled to Peru, where we performed a series of experiments in the Andean highlanders. The experimental objectives, organization and characteristics, and key cohort data from Global REACH's latest research expedition are outlined herein. Fifteen major studies are described that aimed to elucidate the physiological differences in high altitude acclimatization between lowlanders (n = 30) and Andean-born highlanders with (n = 22) and without (n = 45) excessive erythrocytosis. After baseline testing in Kelowna, BC, Canada (344 m), Global REACH travelled to Lima, Peru (∼80 m) and then ascended by automobile to Cerro de Pasco, Peru (∼4300 m), where experiments were conducted over 25 days. The core studies focused on elucidating the mechanism(s) governing cerebral and peripheral vascular function, cardiopulmonary regulation, exercise performance and autonomic control. Despite encountering serious logistical challenges, each of the proposed studies was completed at both sea level and high altitude, amounting to ∼780 study sessions and >3000 h of experimental testing. Participant demographics and data relating to acid-base balance and exercise capacity are presented. The collective findings will contribute to our understanding of how lowlanders and Andean highlanders have adapted under high altitude stress.

THE INFLUENCE OF ANESTHESIA WITH AND WITHOUT MEDETOMIDINE ON CARDIAC STRUCTURE AND FUNCTION IN SANCTUARY CAPTIVE CHIMPANZEES (PAN TROGLODYTES).

Dependent on timing of assessment, anesthetic agents and specifically medetomidine negatively affect cardiac function in great apes. The aim of this study was to determine the influence of tiletamine-zolazepam (TZ) with and without medetomidine on cardiac structure and function in healthy chimpanzees (Pan troglodytes) during a period of relative blood pressure stability. Twenty-four chimpanzees living in an African wildlife sanctuary undergoing routine health assessments were stratified by age, sex, and body mass and randomized to be anesthetized using either TZ (6 mg/kg; n = 13; seven males and six females) or a combination of TZ (2 mg/kg) and medetomidine (TZM; 0.02 mg/kg; n = 11; five males and six females). During health checks, regular heart rate and blood pressure readings were taken and a standardized echocardiogram was performed 20-30 min after induction. Data were compared between the two anesthetic groups using independent-samples t or Mann-Whitney U tests. Although heart rate (mean ± SD; TZ: 76 ± 10 bpm; TZM: 65 ± 14 bpm, P = 0.027), cardiac output (TZ: 3.0 ± 0.7 L/min; TZM: 2.4 ± 0.7 L/min, P = 0.032), and mitral A-wave velocities (TZ: 0.51 ± 0.16 cm/s; TZM: 0.36 ± 0.10 cm/s, P = 0.013) were lower in the TZM group, there were no statistically significant differences in cardiac structure or the remaining functional variables between groups. Furthermore, there were no statistical differences in systolic (TZ 114.6 ± 14.9 mmHg; TZM: 123.0 ± 28.1 mmHg; P = 0.289) or diastolic blood pressure (TZ: 81.8 ± 22.3 mmHg, TZM: 83.8 ± 20.1 mmHg; P = 0.827) between the groups during the echocardiogram. This study has shown that during a period of relative blood pressure stability, during the first 20-30 min after induction there are few differences in measures of cardiac structure and function between protocols using TZ with or without medetomidine in healthy chimpanzees.

Internal carotid and brachial artery shear-dependent vasodilator function in young healthy humans.

KEY POINTS: Brachial artery (BA) shear-mediated dilatation is a widely used assessment of vascular function with links to coronary artery health and cardiovascular risk. Cerebral vascular health is often interrogated using cerebrovascular (middle cerebral artery velocity) reactivity to carbon dioxide. We show that endothelium-dependent diameter (dilator) responses are not significantly related between the internal carotid artery (ICA) and BA; nor are endothelium-independent responses. Additionally, ICA endothelium-dependent responses are not related to middle cerebral artery velocity or ICA blood flow reactivity responses to carbon dioxide. Therefore, assessment of large extracranial cerebral artery vascular health should be quantified via methods specific to the vessel, not via peripheral endothelial function or cerebrovascular reactivity to carbon dioxide. ABSTRACT: This study compared internal carotid artery (ICA) and brachial artery (BA) endothelium-dependent and -independent vasodilation. We hypothesized that endothelium-dependent and -independent vasodilation of the ICA and BA would be neither similar in magnitude nor correlated between vessels. In 19 healthy adults (23 ± 6 years, 24 ± 3 kg/m2 , six female), endothelium-dependent dilatation in the ICA was determined via Duplex ultrasound during transiently elevated shear stress caused by increased partial pressure of end-tidal carbon dioxide using dynamic end-tidal forcing (+9 mmHg; cerebral flow-mediated dilatation, cFMD). BA endothelium-dependent dilatation was assessed via standard flow-mediated dilatation (FMD). Endothelium-independent dilatation in the ICA and BA was assessed concurrently for 10 min following administration of 400 µg sublingual glyceryl trinitrate (GTN). Endothelium-dependent vasodilation of the ICA (3.4 ± 2.4%) was lower than (P = 0.013) and not correlated to that of the BA (7.9 ± 3.3%; r2  = 0.00, P = 0.93). Including baseline diameter and shear-rate area under the curve as covariates maintained the difference between cFMD and FMD (3.3 ± 4.2% vs. 7.8 ± 3.8%, P = 0.03), while including baseline diameter and baseline shear rate-adjusted area under the curve as covariates abolished it (5.9 ± 3.7% vs. 5.9.8 ± 3.5%, P = 0.99). GTN-mediated vasodilation of the ICA (14.3 ± 2.9%) was lower than (P = 0.002) and not correlated to that of the BA (25.5 ± 8.8%; r2  = 0.12, P = 0.19). Adjusting for baseline diameter eliminated the differences in GTN-induced vasodilation (ICA: 20.1 ± 5.8% vs. BA: 20.4 ± 5.5%; P = 0.93). Differences in endothelium-dependent responses, and the lack of correlations between arteries, indicates that endothelium-dependent function cannot be assumed to be related across cerebral and peripheral vasculatures in young, healthy humans.

Acute reductions in haematocrit increase flow-mediated dilatation independent of resting nitric oxide bioavailability in humans.

KEY POINTS: Changes in haematocrit influence nitric oxide signalling through alterations in shear stress stimuli and haemoglobin scavenging of nitric oxide; these two regulatory factors have not been assessed simultaneously Isovolumic haemodilution led to a marked increase in brachial artery flow-mediated dilatation in humans The increase in flow-mediated dilatation occurred in the face of an unaltered shear stress stimulus for vasodilatation and reduced resting steady-state nitric oxide levels in the blood Collectively, our data point towards haemoglobin scavenging of nitric oxide as a key regulatory factor of brachial flow-mediated dilatation and highlight the importance of the simultaneous consideration of nitric oxide production and inactivation when investigating vascular function in humans ABSTRACT: Haemoglobin (Hb) may impact the transduction of endothelium-dependent and nitric oxide (NO)-mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and haematocrit (Hct) would increase brachial artery flow-mediated dilatation (FMD). In 11 healthy males (28 ± 7 years; 23 ± 2 kg m-2 ), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone-based chemiluminescence) were measured before and after isovolumic haemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Haemodilution reduced Hct by 18 ± 2% (P < 0.001) and whole blood viscosity by 22 ± 5% (P < 0.001). Plasma nitrite (P = 0.01), S-nitrosothiols (P = 0.03) and total red blood cell NO (P = 0.001) were collectively reduced by ∼15-40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that haemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium-dependent NO-mediated vasodilatation in healthy humans.

Endothelial function and shear stress in hypobaric hypoxia: time course and impact of plasma volume expansion in men.

High-altitude exposure typically reduces endothelial function, and this is modulated by hemoconcentration resulting from plasma volume contraction. However, the specific impact of hypobaric hypoxia independent of external factors (e.g., cold, varying altitudes, exercise, diet, and dehydration) on endothelial function is unknown. We examined the temporal changes in blood viscosity, shear stress, and endothelial function and the impact of plasma volume expansion (PVX) during exposure to hypobaric hypoxia while controlling for external factors. Eleven healthy men (25 ± 4 yr, mean ± SD) completed two 4-day chamber visits [normoxia (NX) and hypobaric hypoxia (HH; equivalent altitude, 3,500 m)] in a crossover design. Endothelial function was assessed via flow-mediated dilation in response to transient (reactive hyperemia; RH-FMD) and sustained (progressive handgrip exercise; SS-FMD) increases in shear stress before entering and after 1, 6, 12, 48, and 96 h in the chamber. During HH, endothelial function was also measured on the last day after PVX to preexposure levels (1,140 ± 320 mL balanced crystalloid solution). Blood viscosity and arterial shear stress increased on the first day during HH compared with NX and remained elevated at 48 and 96 h (P < 0.005). RH-FMD did not differ during HH compared with NX and was unaffected by PVX despite reductions in blood viscosity (P < 0.05). The stimulus-response slope of increases in shear stress to vasodilation during SS-FMD was preserved in HH and increased by 44 ± 73% following PVX (P = 0.023). These findings suggest that endothelial function is maintained in HH when other stressors are absent and that PVX improves endothelial function in a shear-stress stimulus-specific manner.NEW & NOTEWORTHY Using a normoxic crossover study design, we examined the impact of hypobaric hypoxia (4 days; altitude equivalent, 3,500 m) and hemoconcentration on blood viscosity, shear stress, and endothelial function. Blood viscosity increased during the hypoxic exposure and was accompanied by elevated resting and exercising arterial shear stress. Flow-mediated dilation stimulated by reactive hyperemia and handgrip exercise was preserved throughout the hypoxic exposure. Plasma volume expansion reversed the hypoxia-associated hemoconcentration and selectively increased handgrip exercise flow-mediated dilation.

No impact of acute hyperglycaemia on arterial stiffness in the early and late follicular phases of the menstrual cycle in young females.

NEW FINDINGS: • What is the central question of this study? This is the first study to examine the impact of acute hyperglycaemia on arterial stiffness across the early and late follicular phases of the menstrual cycle. • What is the main finding and its importance? Central and peripheral arterial stiffness were not impacted by acute hyperglycaemia. This indicates that premenopausal women might experience protection against deleterious effects of acute hyperglycaemia, regardless of menstrual cycle phase. This research furthers our understanding of the interaction between nutrient intake, hormonal fluctuation and vascular function in premenopausal women. ABSTRACT: Acute hyperglycaemia may result in transient increases in arterial stiffness. However, research in healthy premenopausal women is lacking, and the impact of menstrual phase [early follicular (EF; low oestrogen) and late follicular (LF; high oestrogen)] on vulnerability to acute hyperglycaemia-induced changes in arterial stiffness is unknown. We hypothesized that an acute hyperglycaemia-induced increase in arterial stiffness in the EF phase would be attenuated in the LF phase. Seventeen healthy, naturally menstruating women [21 ± 1 years of age (mean ± SD)] participated in three experimental visits. During two visits, in the EF and LF phase, arterial stiffness was assessed via central and peripheral (arm and leg) pulse wave velocity (PWV) before and 15, 45, 75 and 105 min after consuming an oral glucose challenge (75 g glucose in 300 ml of solution). Blood samples were taken to assess glucose, insulin, oestrogen and progesterone concentrations. During a third visit in the EF phase, participants ingested 300 ml of water as a time control for PWV. Despite significant increases in blood glucose and insulin (P < 0.001), both central and peripheral arm PWV remained unchanged across time and phase, indicating that neither acute hyperglycaemia nor menstrual phase had an impact on central or peripheral arm arterial stiffness. There was a small effect of phase for peripheral leg PWV, where PWV was lower in the LF phase (P = 0.04, Cohen's d = 0.39); however, and in contrast to recent results in young men, peripheral leg PWV was unaffected by hyperglycaemia. These results suggest that premenopausal women might experience protection from acute hyperglycaemia-induced increases in arterial stiffness.

UBC-Nepal expedition: dynamic cerebral autoregulation is attenuated in lowlanders upon ascent to 5050 m.

PURPOSE: We examined the effects of hypoxaemia on dynamic cerebral autoregulation (dCA) in lowlanders and Sherpa highlanders. We hypothesized that dCA in lowlanders would be reduced to a greater extent in the common carotid artery (CCA) compared to the internal carotid artery (ICA) during acute hypoxia at sea level and at high altitude, whereas Sherpa highlanders would have preserved dCA upon ascent to high altitude. METHODS: dCA was calculated as the change in cerebrovascular conductance during transient hypotension induced via dual thigh-cuff release. Data were collected in 13 healthy lowlanders in normobaric normoxia and hypoxia (FIO2 = 0.11) at sea-level (344 m), and the day after arrival at 3440 m and 5050 m. In addition, 10 healthy Sherpa highlanders were tested at Kathmandu (~ 1400 m), and the day after arrival at 3440 m and 5050 m. RESULTS: The main findings were that: (1) in lowlanders, dCA in the CCA and ICA were both reduced by ~ 35% during normobaric hypoxia exposure at sea-level (P = 0.06 and P = 0.04, respectively); (2) CCA and ICA dCA were both similarly attenuated by ~ 40% at 5050 m in lowlanders, but not 3440 m, compared to sea-level (both P = 0.04); and (3) in Sherpa, high altitude had no impact on CCA dCA (P = 0.275), indicating intact cerebral autoregulation. CONCLUSION: Herein, we provide novel evidence that dCA, assessed via Duplex ultrasound, was attenuated in lowlanders with exposure to normobaric and hypobaric hypoxia, whereas it is potentially preserved in the Sherpa. The clinical implications of attenuated dCA in lowlanders, and the adaptive significance of this response in the Sherpa highlanders, remains to be elucidated.