Philip N Ainslie

University of British Columbia - Okanagan | UBC Okanagan · School of Health and Exercise Sciences

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-dependent and -independe...

The mammalian dive reflex, characterized by bradycardia and peripheral vasoconstriction, occurs in all mammals, including humans, in response to apnea. However, the dive reflex to a single, maximal, dry, dynamic apnea (DYN), and how it compares to a time-matched exercise control trial (EX) or dry static apnea (SA), has not been studied. We examined...

Aim How the cerebral metabolic rates of oxygen and glucose utilization (CMRO 2 and CMR Glc , respectively) are affected by alterations in arterial PCO 2 (PaCO 2 ) 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 ma...

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...

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cyclin...

Periodic breathing during sleep at high altitude is almost universal among sojourners. Here, in the context of acclimatization and adaptation, we provide a contemporary review on periodic breathing at high altitude, and explore whether this is an adaptive or maladaptive process. The mechanism(s), prevalence and role of periodic breathing in acclima...

We examined the extent to which apnoea‐induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra‐elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end‐apnoea hypoxaemic hypercapnia, and hyperoxic...

Pentoxifylline is a non-selective 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...

Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis. Exercise has been shown to activate platelets and stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a potentially powerful link between platelet function and brain...

Cerebral blood velocity (CBv) increases in response to moderate exercise in humans, but the magnitude of change is smaller in children compared to post-pubertal adolescents and adults. Whether sex differences exist in the anterior or posterior CBv response to exercise across pubertal development remains to be determined. We assessed middle cerebral...

Purpose To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). “Controller-gain” sensitivity from...

Passive hyperthermia causes cerebral hypoperfusion primarily from heat‐induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro‐inflamm...

Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia (CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$) are modulated by gonadal hormone activity, while insulin‐like growth factor 1 facilitates exercise‐mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal a...

The purpose of this study was to examine the effect of an acute bout of prolonged sitting with and without exercise breaks on cerebrovascular function in 7‐ to 13‐year‐old children. Forty‐two children and adolescents were recruited to a crossover trial, with 15 girls (mean age 10.1 ± 2.5 years) and 16 boys (mean age 10.5 ± 1.3 years) completing the...

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in‐flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro...

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous PCO2${P_{{\ma...

BACKGROUND: Voluntary asphyxia induced by apnea in competitive breath hold (BH) divers affords a unique opportunity to examine integrated mechanisms underlying the preservation of cerebral bioenergetic function. This study examined to what extent physiological extremes of oxygen (O2) demand and carbon dioxide (CO2) production impact redox homeostas...

Brewster, L. Madden, Anthony R. Bain, Vinicius P. Garcia, Noah M. DeSouza, Michael M. Tymko, Jared J. Greiner, and Philip N. Ainslie. Global REACH 2018: high altitude-related circulating extracellular microvesicles promote a proinflammatory endothelial phenotype in vitro. High Alt Med Biol. 00:000-000, 2023. Introduction: Ascent to high altitude (H...

Neurovascular coupling (NVC) is mediated via nitric oxide signalling, which is independently influenced by sex hormones and exercise training. Whether exercise training differentially modifies NVC pre- vs. post-puberty, where levels of circulating sex hormones will differ greatly within- and between-sexes, remains to be determined. Therefore, we in...

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 S-nitrosothiol (RSNO) and nitrite (NO2-) signaling in the regulation of cerebral hypoxic va...

Background Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiopulmonary and cerebrovascular disease-related morbidity and mortality. The factors that initiate, promote, and accelerate vascular diseases and events in SCI are poorly understood. Clinical interest in circulating endothelial cell-derived microvesicles...

Cerebral blood flow (CBF) increases during hypoxia to counteract the reduction in arterial oxygen content. The onset of tissue hypoxemia coincides with the stabilization of hypoxia-inducible factor (HIF) and transcription of downstream HIF-mediated processes. It has yet to be determined, whether HIF down- or upregulation can modulate hypoxic vasodi...

Vizcardo-Galindo, Gustavo A., Connor A. Howe, Ryan L. Hoiland, Howard H. Carter, Christopher K. Willie, Philip N. Ainslie, and Joshua C. Tremblay. Impact of oxygen supplementation on brachial artery hemodynamics and vascular function during ascent to 5,050 m. High Alt Med Biol. 24:27-36, 2023.-High-altitude trekking alters upper limb hemodynamics a...

High‐altitude (HA) hypoxia may alter the structural–functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex‐, age‐ and body mass index‐matched healthy highlanders (n = 9) native to CdP...

Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signalling, the primary mechanism mediating sympathetic vasoconstriction at sea-level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular con...

Investigation of pulmonary gas exchange efficacy usually requires arterial blood gas analysis (aBGA) to determine arterial partial pressure of oxygen (mPaO2) and compute the Riley alveolar-to-arterial oxygen difference (A-aDO2); that is a demanding and invasive procedure. A noninvasive approach (AGM100), allowing the calculation of PaO2 (cPaO2) der...

Intermittent fasting and exercise provide neuroprotection from age‐related cognitive decline. A link between these two seemingly distinct stressors is their capability to steer the brain away from exclusively glucose metabolism. This cerebral substrate switch has been implicated in upregulating brain‐derived neurotrophic factor (BDNF), a protein in...

Prolonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n = 20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherp...

Cervical spinal cord injury (SCI) leads to autonomic cardiovascular dysfunction that underlies the 3-4 fold elevated risk of cardiovascular disease in this population. Reduced common carotid artery (CCA) dilatory responsiveness during the cold-pressor test (CPT) is associated with greater cardiovascular disease risk and progression. The cardiovascu...

Physical activity is the most common source of heat strain for humans. The thermal strain of physical activity causes over-breathing (hyperventilation) and this has adverse physiological repercussions. The mechanisms underlying heat-induced hyperventilation during exercise are unknown, but recent evidence supports a primary role of carotid body hyp...

This study investigated the influence of acute reductions in arterial O 2 content (CaO 2 ) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO 2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m ² ). Radial artery and internal jugular vein catheters provided measurement of blo...

New findings: What is the central question of this study? We assessed the contributions of shear stress to brachial artery vasodilation during hypercapnia, using a within-individual bilateral experimental design, with increases in shear stress in one artery prevented via manual arterial compression. We repeated this design with and without an α₁-a...

Intracranial blood velocity reactivity to a steady-state hypercapnic stimulus has been shown to be similar in children and adults, but the onset response to hypercapnia is slower in the child. Given the vasodilatory effect of hypercapnia on the cerebrovasculature, assessment of vessel diameter, and blood flow are vital to fully elucidate whether th...

New findings: What is new and noteworthy? What is the central question of this study? Does the hyperbaric, hypercapnic, acidotic, hypoxic stress of apnoea diving lead to greater pulmonary vasoreactivity and increased right-heart work in apnoea divers? What is the main finding and its importance? Compared to sex- and age-matched controls, Divers ha...

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid–base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole‐body heating and cooling, indicating that altered carotid body function...

Chronic exposure to hypoxia (high‐altitude, HA; >4000 m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signal...

This chapter discusses the regulation of cerebral metabolism and fuel utilization at rest and during dynamic whole-body exercise in humans. The relative contributions of cerebral metabolic rates of key substrates (oxygen, glucose, lactate, ketone bodies) are outlined with respect to rest and exercise. A brief overview of the current gold-standard t...

Introduction: Damping of pulsatile flow between extracranial and intracranial cerebral arteries is an essential allostatic mechanism protecting cerebral microvessels from recalcitrant hemodynamics. The ratio of pulsatility between proximal and distal cerebral arteries may provide a measure of cerebrovascular hemodynamic damping. This might prove u...

Myocardial oxygen delivery is primarily regulated through changes in vascular tone to match increased metabolic demands. In males, activation of the muscle metaboreflex during acute isocapnic hypoxia results in a paradoxical coronary vasoconstriction. Whether coronary blood velocity is reduced by metaboreflex activation following travel and/or adap...

Andeans with chronic mountain sickness (CMS) and polycythemia have similar maximal oxygen uptakes to healthy Andeans. Therefore, this study aimed to explore potential adaptations in convective oxygen transport, with a specific focus on sympathetically mediated vasoconstriction of non-active skeletal muscle. In Andeans with (CMS+: n=7) and without (...

Objectives During apnea diving, a patent foramen ovale (PFO) may function as a pressure relief valve under conditions of high pulmonary pressure, preserving left-ventricular output. However, PFO prevalence in apneic divers has not been previously reported. We aimed to determine the prevalence of PFO in apneic divers compared to non-diver controls....

Steele, Andrew R., Philip N. Ainslie, Rachel Stone, Kaitlyn Tymko, Courtney Tymko, Connor A. Howe, David MacLeod, James D. Anholm, Christopher Gasho, and Michael M. Tymko. Global REACH 2018: characterizing acid-base balance over 21 days at 4,300 m in lowlanders. High Alt Med Biol. 00:000-000, 2022. Introduction: High altitude exposure results in hy...

Voluntary asphyxia imposed by static apnea challenges blood-brain barrier (BBB) integrity in humans through transient extremes of hypertension, hypoxemia and hypercapnia. In the present study, ten ultra-elite breath-hold divers performed two maximal dry apneas preceded by normoxic normoventilation (NX: severe hypoxemia and hypercapnia) and hyperoxi...

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH(a) 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 t...

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 t...

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO 3 ⁻ ]) and carbon dioxide tension (PCO 2 ) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO 2 (PaCO 2 ) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaus...

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 you...

figure legend. Acid–base balance and cerebrovascular regulation in humans. The cerebral circulation is exceptionally sensitive to arterial PCO2 (PaCO2) throughout the cerebrovascular tree; the integrative relationship between PaCO2 and pH on cerebral blood flow (CBF) regulation acts to stabilize CO2 gradients and thus regulate pH across the blood–b...

Ascent to high altitude can adversely affect cardio- and cerebrovascular health, particularly in those with pre-existing disease. Pathologic vascular responses to acute and subacute high altitude exposure include, endothelial dysfunction, cerebral and pulmonary edema as well as pulmonary hypertension. Changes in vascular endothelial cell function,...

Individuals with cervical spinal cord injury (SCI) are at an increased risk for cardiovascular disease. Exercise is well-established for preventing cardiovascular disease; however, there are limited straightforward and safe exercise approaches for increasing the activity of the cardiorespiratory system after cervical SCI. The objective of this stud...

Introduction: Previous research has highlighted squat-stand maneuvers (SSM) augment coherence values within the cerebral pressure-flow relationship to ~0.99. However, it is unknown the extent the entrainment of physiological systems is due to mean arterial pressure (MAP) independently, or also due to heart rate (HR) and/or partial pressure of carbo...

We explored the influence of sex and maturation on resting cervical artery hemodynamics (common carotid artery, CCA; internal carotid artery, ICA; and vertebral artery, VA) and free-living physical activity and sedentary behavior in children 6-17 years of age. Additionally, we investigated the relationship between physical activity and sedentary be...

Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow and brain‐derived neurotrophic factor (BDNF). Ketone supplements containing β‐hydroxybutyrate (β‐OHB) are a purported therapeutic strategy for improving brain health in at‐risk populations. We tested the hypothesis that short‐t...

Aim: It is generally considered that regular exercise maintains brain health and reduces the risk of cerebrovascular diseases such as stroke and dementia. Since the benefits of different 'types' of exercise are unclear, we sought to compare the impacts of endurance and resistance training on cerebrovascular function. Methods: In a randomized and...

Background Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpa at high altitude. In contrast, the pulmonary vasculature of Andeans suffering with chronic mountain sickness is resistant to iron administration. While pulmonary vascular remodeling and hypertension are characteristic features of c...

Haemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signalling 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: (i) at sea level, in normoxia and isocapnic hypoxia w...

Key points Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involvin...

The high-altitude maladaptation syndrome known as chronic mountain sickness (CMS) is characterized by polycythemia and is associated with proteinuria despite unaltered glomerular filtration rate. However, it remains unclear if indigenous highlanders with CMS have altered volume regulatory hormones. We assessed N-terminal pro-B-type natriuretic pept...

In 1959, Niels Lassen illustrated the cerebral autoregulation curve in the classic review article entitled Cerebral Blood Flow and Oxygen Consumption in Man. This concept suggested a relatively broad mean arterial pressure range (~60–150 mmHg) wherein cerebral blood flow remains constant. However, the assumption that this wide cerebral autoregulati...

Rationale Secondary brain hypoxia portends significant mortality in ischemic brain diseases; yet, our understanding of hypoxic ischemic brain injury (HIBI) pathophysiology in humans remains rudimentary. Objective To quantify the impact of secondary brain hypoxia on injury to the neurovascular unit in patients with HIBI. Methods and Results We con...

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...

Key points We investigated the influence of arterial PCO2 (PaCO2) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and...

Introduction Populations suffering from polycythemia such as polycythemia vera, Chuvash polycythemia, and chronic mountain sickness (CMS) suffer exercise fatigue and reduced exercise capacity. Potential mechanisms for reduced exercise capacity include the negative influences of high hematocrit, elevated blood viscosity, and increased sympathetic ac...

We tested the hypotheses that 1) cutaneous microvascular function is impaired by acute normobaric and chronic hypobaric hypoxia and 2) that the superoxide free radical (via NADPH oxidase or xanthine oxidase) contributes to this impairment via nitric oxide (NO) scavenging. Local heating-induced cutaneous hyperemia (39°C) was measured in the forearm...

Breath-hold diving involves highly integrative physiology and extreme responses to both exercise and asphyxia during progressive elevations in hydrostatic pressure. With astonishing depth records exceeding 100 m, and up to 214 m on a single breath, the human capacity for deep breath-hold diving continues to refute expectations. The physiological ch...