UBC-Nepal expedition: The use of oral antioxidants does not alter cerebrovascular function at sea-level or high-altitude

Hypoxia is associated with an increased systemic and cerebral formation of free radicals and associated reactants that may be linked to impaired cerebral vascular function a neurological sequela. To what extent oral antioxidants prophylaxis impacts cerebrovascular function in humans throughout the course of acclimatization to the hypoxia of terrestrial high-altitude has not been examined. Thus, the purpose of the current study was to examine the influence of orally ingested antioxidants at clinically relevant doses (vitamin C, E, and alpha-lipoic acid) on cerebrovascular regulation at sea-level (344 m; n = 12; female n = 2 participants), and at high altitude (5050 m; n = 9; female n = 2), in a randomized, placebo-controlled, and double-blinded crossover design. Hypercapnic and hypoxic cerebrovascular reactivity tests of the internal carotid (ICA)] were conducted at sea-level, while global and regional cerebral blood flow [i.e. ICA and vertebral artery (VA)] were assessed after 10–12 days following arrival at 5050 m. At sea-level, acute administration of antioxidants did not alter cerebral hypoxic cerebrovascular reactivity (pre vs. post: 1.5 ± 0.7 vs. 1.2 ± 0.8 %∆CBF/-%∆SpO2; P = 0.96), or cerebral hypercapnic cerebrovascular reactivity (pre vs. post: 5.7 ± 2.0 vs. 5.8 ± 1.9 %∆CBF/∆mmHg; P = 0.33). Furthermore, global cerebral blood flow (P = 0.43), as well as cerebral vascular conductance (ICA P = 0.08; VA P = 0.32), were unaltered at 5050 m following antioxidant administration. In conclusion, these data show that an oral antioxidant cocktail known to attenuate systemic oxidative stress failed to alter cerebrovascular function at sea-level and cerebral blood flow during acclimatization to high-altitude

Impact of transient hypotension on regional cerebral blood flow in humans

Abstract We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow (CBF) and intracranial velocities. Participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities (transcranial Doppler; TCD), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery (ICA) and vertebral artery (VA) blood flow (ICA BF and VA BF respectively) were also obtained. Overall, blood pressure was reduced by ∼20 % from baseline in both trials (P < 0.001). In the isocapnic trial, end-tidal carbon dioxide was successfully clamped at baseline with hypotension, whereas in the poikilocapnic trial it was reduced by 11.1 mmHg (P < 0.001) with hypotension. The decline in the ICA BF with hypotension was comparable between trials (−139 + − 82 ml; ∼30 %; P < 0.0001); however, the decline in the VA BF was −28 + − 22 ml/min (∼21 %) greater in the poikilocapnic trial compared with the isocapnic trial (P = 0.002). Regardless of trial, the blood flow reductions in ICA (−26 + − 14 %) and VA (−27 + − 14 %) were greater than the decline in MCA (−21 + − 15 %) and PCA (−19 + − 10 %) velocities respectively (P 0.01). Significant reductions in the diameter of both the ICA (∼5 %) and the VA (∼7 %) contributed to the decline in cerebral perfusion with systemic hypotension, independent of hypocapnia. In summary, our findings indicate that blood flow in the VA, unlike the ICA, is sensitive to changes hypotension and hypocapnia. We show for the first time that the decline in global CBF with hypotension is influenced by arterial constriction in the ICA and VA. Additionally, our findings suggest TCD measures of blood flow velocity may modestly underestimate changes in CBF during hypotension with and without hypocapnia, particularly in the posterior circulation

Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged ( 2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders(Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation(FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima–media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO2 –) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3–4 (acute high altitude) and 12–14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders’ FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s−1; P = 0.001). These changes persisted at days 12–14, and after allometricallyscaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio ( 19%, P 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO2 – increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r=−0.53) and chronic (n = 7, r=−0.69; P 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n=11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspiredO2 fraction (FIO2 )=0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure when compared to normoxic baseline (5.7±1.6 vs. 8.0 ±1.3%; P < 0.01); this decline in FMD was largely reversed following α1-adrenoreceptor blockade. In conclusion, high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation. Although a lifetime of high-altitude exposure neither intensifies nor attenuates the impairments seen with short-term exposure, chronic high-altitude exposure appears to be associated with arterial remodelling

Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas

The incidence of blood flow through intracardiac shunt and intrapulmonary arteriovenous anastomoses (IPAVA) may differ between Sherpas permanently residing at high altitude (HA) and sea-level (SL) inhabitants as a result of evolutionary pressure to improve gas exchange and/or resting pulmonary haemodynamics. To test this hypothesis we compared sea-level inhabitants at SL (SL-SL; n = 17), during acute isocapnic hypoxia (SL-HX; n = 7) and following 3 weeks at 5050 m (SL-HA; n = 8 non-PFO subjects) to Sherpas at 5050 m (n = 14). inline image, heart rate, pulmonary artery systolic pressure (PASP) and cardiac index (Qi) were measured during 5 min of room air breathing at SL and HA, during 20 min of isocapnic hypoxia (SL-HX; inline image = 47 mmHg) and during 5 min of hyperoxia (inline image = 1.0; Sherpas only). Intracardiac shunt and IPAVA blood flow was evaluated by agitated saline contrast echocardiography. Although PASP was similar between groups at HA (Sherpas: 30.0 ± 6.0 mmHg; SL-HA: 32.7 ± 4.2 mmHg; P = 0.27), it was greater than SL-SL (19.4 ± 2.1 mmHg; P < 0.001). The proportion of subjects with intracardiac shunt was similar between groups (SL-SL: 41%; Sherpas: 50%). In the remaining subjects, IPAVA blood flow was found in 100% of subjects during acute isocapnic hypoxia at SL, but in only 4 of 7 Sherpas and 1 of 8 SL-HA subjects at rest. In conclusion, differences in resting pulmonary vascular regulation, intracardiac shunt and IPAVA blood flow do not appear to account for any adaptation to HA in Sherpas. Despite elevated pulmonary pressures and profound hypoxaemia, IPAVA blood flow in all subjects at HA was lower than expected compared to acute normobaric hypoxia

Chemoreceptor responsiveness at sea level does not predict the pulmonary pressure response to high altitude

The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting peripheral oxyhemoglobin saturation (SpO2) at HA would correlate better than HVR at SL to PASP at HA. In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min·-%SpO2 -1) and resting PASP using echocardiography. Both resting SpO2 and PASP measures were repeated on day 2 (n=10), days 4-8 (n=12), and 2-3 weeks (n=8) after arrival at 5050m. These data were also collected at 5050m on life-long HA residents (Sherpa; n=21). Compared to SL, SpO2 decreased from 98.6 to 80.5% (P<0.001), while PASP increased from 21.7 to 34.0mmHg (P<0.001) after 2-3 weeks at 5050m. Isocapnic HVR at SL was not related to SpO2 or PASP at any time point at 5050m (all P>0.05). Sherpa had lower PASP (P<0.01) than lowlanders on days 4-8 despite similar SpO2. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL, but lower than lowlanders at all HA time points. At 5050m, whilst SpO2 was not related to PASP in lowlanders at any point (all R2=0.50), there was a weak relationship in the Sherpa (R2=0.16; P=0.07). We conclude that neither HVR at SL nor resting SpO2 at HA correlates with elevations in PASP at HA

Hypoxia, not pulmonary vascular pressure induces blood flow through intrapulmonary arteriovenous anastomoses

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times-a-day for 48 h) to prevent increases in PASP, and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ+HCO3-) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic-hypoxia condition to determine pH, [HCO3-], and PaCO2. AZ decreased pH (-0.08 ± 0.01), [HCO3-] (-7.1 ± 0.7 mmol/l), and PaCO2 (-4.5 ± 1.4 mmHg; p<0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (p<0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (p<0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (p<0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H+ concentration or PaCO2. Abbreviations list: AZ, acetazolamide; FEV1, forced expiratory volume in 1 second; FIO2, fraction of inspired oxygen; FVC, forced vital capacity; Hb, total haemoglobin; HPV, hypoxic pulmonary vasoconstriction; HR, heart rate; IPAVA, intrapulmonary arteriovenous anastomoses; MAP, mean arterial pressure; PASP, pulmonary artery systolic pressure; PETCO2, end-tidal partial pressure of carbon dioxide; PETO2, end-tidal partial pressure of oxygen; PFO, patent foramen ovale; PVR, pulmonary vascular resistance; Q̇c, cardiac output; RVOT, right ventricular outflow tract; SpO2, oxyhaemoglobin saturation; SV, stroke volume; TRV, tricuspid regurgitant velocity; V̇E, minute ventilation; VTI, velocity-time integra

Understanding Canine ‘Reactivity’: Species-Specific Behaviour or Human Inconvenience?

Dogs are often referred to as “human’s best friend,” with many households in the United Kingdom and worldwide including a dog. Yet, whilst research highlights the myriad of human health benefits associated with canine companionship, many dogs are relinquished, or euthanized, for purported behavioral problems. A key behavior often cited in these situations is Reactivity, despite a lack of consensus in the literature (or in the lay population) as to exactly what is encompassed within this term. Resultantly, this paper reports on an online survey to investigate how the term Reactivity is understood by humans. Following the completion of a thematic analysis, six sub-themes were developed, forming three overarching theme clusters, namely; Canine Characteristics, The Importance of Human Perception and Human Capability. In sum, this research highlights the complex, nuanced and, sometimes, contradictory nature of understanding around the label of Reactivity, encompassing both canine and human factors. As such, conclusions include the proposal of a preliminary Perceived Reactivity Framework to conceptualize this seemingly multi-faceted concept

Post-exercise blood pressure reduction is greater following intermittent than continuous exercise and is influenced less by diurnal variation

Recently, we reported that circadian variation exists in the response of blood pressure (BP) following a bout of uninterrupted exercise. The usual phenomenon of post-exercise hypotension was absent or reversed when such exercise was performed between 04:00-08:00 h. Nevertheless, research examining BP changes following bouts of intermittent exercise at different times of the day is scarce, even though this type of activity is probably more popular. Therefore, we aimed to compare post-exercise BP reductions of continuous (CONT) and intermittent (INT) exercise protocols performed at 08:00 h and 16:00 h. At both of these times of day, eight normotensive males completed 30 min of continuous cycling in the CONT and three 10 min bouts of cycling separated by 10 min of rest in the INT protocol. The exercise intensity was set at 70% VO2peak during both protocols. Heart rate, systolic (S) and diastolic (D) BP, and mean arterial pressure (MAP) were measured 5 min before and 20 min after exercise. Changes from pre-exercise baseline were analyzed using linear mixed modeling. MAP was 8±1 mm Hg lower following INT compared with CONT exercise (p<0.05). SBP and DBP were also significantly lower following INT compared with CONT exercise (p<0.05). Diurnal variation in MAP was evident, with attenuated hypotension being observed after morning exercise (p<0.05), although this diurnal variation was less marked following INT compared with CONT exercise (p<0.05). We conclude that intermittent exercise mediates greater post-exercise hypotension compared with a single continuous bout of equivalent work and that this protocol-dependent difference is greatest in the afternoon. Therefore, a bout of afternoon exercise that is occasionally interrupted with short rest periods is recommended for lowering BP acutely