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

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

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

Slow breathing as a means to improve orthostatic tolerance:a randomized sham-controlled trial

Endogenous oscillations in blood pressure (BP) and cerebral blood flow have been associated with improved orthostatic tolerance. Although slow breathing induces such responses, it has not been tested as a therapeutic strategy to improve orthostatic tolerance. With the use of a randomized, crossover sham-controlled design, we tested the hypothesis that breathing at six breaths/min (vs. spontaneous breathing) would improve orthostatic tolerance via inducing oscillations in mean arterial BP (MAP) and cerebral blood flow. Sixteen healthy participants (aged 25 ± 4 yr; mean ± SD) had continuous beat-to-beat measurements of middle cerebral artery blood velocity (MCAv), BP (finometer), heart rate (ECG), and end-tidal carbon dioxide partial pressure during an incremental orthostatic stress test to presyncope by combining head-up tilt with incremental lower-body negative pressure. Tolerance time to presyncope was improved (+15%) with slow breathing compared with spontaneous breathing (29.2 ± 5.4 vs. 33.7 ± 6.0 min; P &lt; 0.01). The improved tolerance was reflected in elevations in low-frequency (LF; 0.07-0.2 Hz) oscillations of MAP and mean MCAv, improved metrics of dynamic cerebrovascular control (increased LF phase and reduced LF gain), and a reduced rate of decline for MCAv (−0.60 ± 0.27 vs. −0.99 ± 0.51 cm·s−1·min−1; P &lt; 0.01) and MAP (−0.50 ± 0.37 vs. −1.03 ± 0.80 mmHg/min; P = 0.01 vs. spontaneous breathing) across time from baseline to presyncope. Our findings show that orthostatic tolerance can be improved within healthy individuals with a simple, nonpharmacological breathing strategy. The mechanisms underlying this improvement are likely mediated via the generation of negative intrathoracic pressure during slow and deep breathing and the related beneficial impact on cerebrovascular and autonomic function. </jats:p

Correction to: Cerebral pressure-flow relationship in lowlanders and natives at high altitude

We investigated if dynamic cerebral pressure–flow relationships in lowlanders are altered at high altitude (HA), differ in HA natives and after return to sea level (SL). Lowlanders were tested at SL (n=16), arrival to 5,050 m, after 2-week acclimatization (with and without end-tidal PO(2) normalization), and upon SL return. High-altitude natives (n=16) were tested at 5,050 m. Testing sessions involved resting spontaneous and driven (squat–stand maneuvers at very low (VLF, 0.05 Hz) and low (LF, 0.10 Hz) frequencies) measures to maximize blood pressure (BP) variability and improve assessment of the pressure–flow relationship using transfer function analysis (TFA). Blood flow velocity was assessed in the middle (MCAv) and posterior (PCAv) cerebral arteries. Spontaneous VLF and LF phases were reduced and coherence was elevated with acclimatization to HA (P<0.05), indicating impaired pressure–flow coupling. However, when BP was driven, both the frequency- and time-domain metrics were unaltered and comparable with HA natives. Acute mountain sickness was unrelated to TFA metrics. In conclusion, the driven cerebral pressure–flow relationship (in both frequency and time domains) is unaltered at 5,050 m in lowlanders and HA natives. Our findings indicate that spontaneous changes in TFA metrics do not necessarily reflect physiologically important alterations in the capacity of the brain to regulate BP