Micro- and macrovascular function in the highest city in the world: a cross sectional study.

Background: Since vascular responses to hypoxia in both healthy high-altitude natives and chronic mountain sickness (a maladaptive high-altitude pathology characterised by excessive erythrocytosis and the presence of symptoms-CMS) remain unclear, the role of inflammation and oxidative/nitrosative stress on the endothelium- and - responses in both the micro- and macrocirculation, in healthy Andeans at different altitudes and in CMS patients, was examined.

Methods: 94 men were included: 18 lowlanders (LL), 38 healthy highlanders permanently living at 3800 m (n = 21-HL-3800) or in La Rinconada, the highest city in the world (5100-5300 m) (n = 17-HL-5100/No CMS). Moreover, 14 participants with mild (Mild CMS) and 24 with moderate to severe CMS (Mod/Sev CMS) were recruited.

Evidence for direct CO -mediated alterations in cerebral oxidative metabolism in humans.

Aim: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO and CMR, respectively) are affected by alterations in arterial PCO (PaCO) is equivocal and therefore was the primary question of this study.

Methods: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady-state alterations in PaCO ranging between 30 and 60 mmHg.

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.

Hemoglobin and cerebral hypoxic vasodilation in humans: Evidence for nitric oxide-dependent and -nitrosothiol mediated signal transduction.

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based -nitrosothiol (RSNO) and nitrite () signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and .

Cerebral endothelium-dependent function and reactivity to hypercapnia: the role of α-adrenoreceptors.

We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function [cerebral shear-mediated dilation (cSMD)] in the internal carotid artery (ICA) with and without systemic α-adrenoreceptor blockade via Prazosin. We hypothesized that CVR would be reduced, whereas cSMD would remain unchanged, after Prazosin administration when compared with placebo. In 15 healthy adults (3 female, 26 ± 4 years), we conducted ICA duplex ultrasound during CVR [target +10 mmHg partial pressure of end-tidal carbon dioxide ([Formula: see text]) above baseline, 5 min] and cSMD (+9 mmHg [Formula: see text] above baseline, 30 s) using dynamic end-tidal forcing with and without α-adrenergic blockade (Prazosin; 0.

Cerebral O and CO transport in isovolumic haemodilution: Compensation of cerebral delivery of O and maintenance of cerebrovascular reactivity to CO.

This study investigated the influence of acute reductions in arterial O content (CaO) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m). Radial artery and internal jugular vein catheters provided measurement of blood pressure and gases, quantification of cerebral metabolism, cerebral CO washout, and trans-cerebral nitrite exchange (ozone based chemiluminescence). Prior to and following haemodilution, the partial pressure of arterial CO (PaCO) was elevated with dynamic end-tidal forcing while gCBF was measured with duplex ultrasound.

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).

The human blood transcriptome exhibits time-of-day-dependent response to hypoxia: Lessons from the highest city in the world.

High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood transcriptome upon an expedition to the highest city in the world, La Rinconada, Peru, which is 5,100 m above sea level.

Global REACH 2018: Characterizing Acid-Base Balance Over 21 Days at 4,300 m in Lowlanders.

Steele, Andrew R., Philip N. Ainslie, Rachel Stone, Kaitlyn Tymko, Courtney Tymko, Connor A.

Acid-base balance at high altitude in lowlanders and indigenous highlanders.

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (∼3,800, ∼4,300, and ∼5,000 m).

Trans-cerebral HCO and PCO exchange during acute respiratory acidosis and exercise-induced metabolic acidosis in humans.

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO]) and carbon dioxide tension (PCO) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO (PaCO) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO] by 0.15 ± 0.

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

Cerebrovascular CO 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.

Global Research Expedition on Altitude-related Chronic Health 2018 Iron Infusion at High Altitude Reduces Hypoxic Pulmonary Vasoconstriction Equally in Both Lowlanders and Healthy Andean Highlanders.

Background: Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andean individuals with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andean individuals, to our knowledge, has not been investigated.

The influence of hemoconcentration on hypoxic pulmonary vasoconstriction in acute, prolonged, and lifelong hypoxemia.

Hemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signaling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: ) at sea level, in normoxia and isocapnic hypoxia with and without isovolumic hemodilution ( = 10, aged 29 ± 7 yr); ) at altitude (6 ± 2 days acclimatization at 5,050 m), before and during hypervolumic hemodilution ( = 11, aged 27 ± 5 yr) with room air and additional hypoxia [fraction of inspired oxygen ([Formula: see text])= 0.15]; and ) at altitude (4,340 m) in Andean high-altitude natives with excessive erythrocytosis (EE; = 6, aged 39 ± 17 yr), before and during isovolumic hemodilution with room air and hyperoxia (end-tidal Po = 100 mmHg).

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

Key Points: We investigated the influence of arterial ( ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in prior to and following intravenous NaHCO to acutely elevate arterial pH and [HCO ]. The NVC response was not altered following NaHCO between stepwise stages; therefore, NVC is acutely mediated by rather than the prevailing arterial [H ]/pH.

Temporal changes in pulmonary gas exchange efficiency when breath-hold diving below residual volume.

New Findings: What is the central question of this study? How does deep breath-hold diving impact cardiopulmonary function, both acutely and over the subsequent 2.5 hours post-dive? What is the main finding and its importance? Breath-hold diving, to depths below residual volume, is associated with acute impairments in pulmonary gas exchange, which typically resolve within 2.5 hours.

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 ( ) with and without acutely elevated arterial pH and bicarbonate ([HCO ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in (i.e.

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.

Global REACH 2018: The carotid artery diameter response to the cold pressor test is governed by arterial blood pressure during normoxic but not hypoxic conditions in healthy lowlanders and Andean highlanders.

New Findings: What is the central question of this study? What is the impact of oxygen on the circulatory responses to an isocapnic cold pressor test (CPT) in lowlanders and Andean highlanders? What is the main finding and its importance? Overall, the circulatory responses to an isocapnic CPT were largely unaltered with acute normobaric hypoxia and chronic hypobaric hypoxia exposure in lowlanders. However, the relationship between mean arterial pressure and common carotid artery diameter was dampened in hypoxic conditions. Furthermore, there were no differences in the circulatory responses to the CPT between lowlanders and Andean highlanders with lifelong exposure to high altitude.

Nitric oxide is fundamental to neurovascular coupling in humans.

Key Points: Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular coupling in humans. Isovolumic haemodilution did not alter neurovascular coupling.

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

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 ), 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.

Global REACH 2018: The Effect of an Expiratory Resistance Mask with Dead Space on Sleep and Acute Mountain Sickness During Acute Exposure to Hypobaric Hypoxia.

Carr, Jay, Rachel Stone, Courtney Tymko, Kaitlyn Tymko, Geoff B. Coombs, Ryan L. Hoiland, Connor A.