We examined the between-day reproducibility of active (squat-stand maneuvers)- and passive [oscillatory lower-body negative pressure (OLBNP) maneuvers]-driven oscillations in blood pressure. These relationships were examined in both younger (n = 10; 25 ± 3 yr) and older (n = 9; 66 ± 4 yr) adults. Each testing protocol incorporated rest (5 min), followed by driven maneuvers at 0.05 (5 min) and 0.10 (5 min) Hz to increase blood-pressure variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal partial pressure of CO2 were monitored. The pressure-flow relationship was quantified in the very low (0.02-0.07 Hz) and low (0.07-0.20 Hz) frequencies (LF; spontaneous data) and at 0.05 and 0.10 Hz (driven maneuvers point estimates). Although there were no between-age differences, very few spontaneous and OLBNP transfer function metrics met the criteria for acceptable reproducibility, as reflected in a between-day, within-subject coefficient of variation (CoV) of <20%. Combined CoV data consist of LF coherence (15.1 ± 12.2%), LF gain (15.1 ± 12.2%), and LF normalized gain (18.5 ± 10.9%); OLBNP data consist of 0.05 (12.1 ± 15.%) and 0.10 (4.7 ± 7.8%) Hz coherence. In contrast, the squat-stand maneuvers revealed that all metrics (coherence: 0.6 ± 0.5 and 0.3 ± 0.5%; gain: 17.4 ± 12.3 and 12.7 ± 11.0%; normalized gain: 16.7 ± 10.9 and 15.7 ± 11.0%; and phase: 11.6 ± 10.2 and 17.3 ± 10.8%) at 0.05 and 0.10 Hz, respectively, were considered biologically acceptable for reproducibility. These findings have important implications for the reliable assessment and interpretation of cerebral pressure-flow dynamics in humans.

Rationale: Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. Objective: To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. Methods and Results: We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+β adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: −52.7±19.6%, ACh2: −25.4±38.7%, ACh3: −35.1±34.7%, all P ≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: −36.4%, P =0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade ( P =0.012), but this effect was not observed in the EE Andeans. Conclusions: These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.

Key Points Summary-Our objective was to quantify endothelial function (via brachial artery flow-mediated dilatation) at sea-level (344m) and high-altitude (3800m) at rest and following both maximal exercise and 30-minutes of moderate-intensity cycling exercise with and without administration of an 1-adrenergic blockade.-Brachial endothelial function did not differ between sea-level and high-altitude at rest, nor following maximal exercise.-At sea-level, endothelial function decreased following 30-minutes of moderate-intensity exercise, and this decrease was abolished with 1-adrenergic blockade. At high-altitude, endothelial function did not decrease immediately post 30-minutes of moderate-intensity exercise, and administration of 1-adrenergic blockade resulted in an increase in flow mediated dilatation.-Our data indicates that post-exercise endothelial function is modified at high-altitude (i.e. prolonged hypoxemia). The current study helps elucidate the physiological mechanisms associated with high-altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function. AbstractWe examined the hypotheses that 1) at rest, endothelial function would be impaired at high-altitude compared to sea-level, 2) endothelial function would be reduced to a greater extent at sea-level compared to high-altitude after maximal exercise, and 3) reductions in endothelial function following moderate-intensity exercise at both sea-level and high-altitude are mediated via an 1-adrenergic pathway. In a double-blinded, counter-balanced, randomized and placebo-controlled design, nine healthy participants performed a maximal-exercise test, and two 30-minute sessions of semi-recumbent cycling exercise at 50% peak Watt following either placebo or 1-adrenergic blockade (prazosin; 0.05mg/kg). These experiments were completed at both sea-level (344m) and high-altitude (3800m). Blood pressure (finger photoplethysmography), heart rate (electrocardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (ultrasound) were recorded prior to, during, and following exercise. Endothelial function assessed by brachial artery flow-mediated dilatation (FMD) was measured prior to, immediately following, and 60-minutes post-exercise. Our findings were: 1) at rest, FMD remained unchanged between sea-level and high-altitude (placebo P=0.287; prazosin: P=0.110); 2) FMD remained unchanged after maximal exercise at sea-level and high-altitude (P=0.244); 3) the 2.90.8% (P=0.043) reduction in FMD immediately after moderate-intensity exercise at sea-level was abolished via 1-adrenergic blockade. Conversely, at high-altitude, FMD was unaltered following moderate-intensity exercise, and administration of 1-adrenergic blockade elevated FMD (P=0.032). Our results suggest endothelial function is differentially affected by exercise when exposed to hypobaric hypoxia. These findings have implications for understanding the chronic impacts of hypoxemia on exercise...

The cerebral pressure-flow relationship can be quantified as a high-pass filter, where slow oscillations are buffered (<0.20 Hz) and faster oscillations are passed through relatively unimpeded. During moderate intensity exercise, previous studies have reported paradoxical transfer function analysis (TFA) findings (altered phase or intact gain). This study aimed to determine whether these previous findings accurately represent this relationship. Both younger (20-30 yr; n = 10) and older (62-72 yr; n = 9) adults were examined. To enhance the signal-to-noise ratio, large oscillations in blood pressure (via oscillatory lower body negative pressure; OLBNP) were induced during steady-state moderate intensity supine exercise (∼45-50% of heart rate reserve). Beat-to-beat blood pressure, cerebral blood velocity, and end-tidal Pco2 were monitored. Very low frequency (0.02-0.07 Hz) and low frequency (0.07-0.20 Hz) range spontaneous data were quantified. Driven OLBNP point estimates were sampled at 0.05 and 0.10 Hz. The OLBNP maneuvers augmented coherence to >0.97 at 0.05 Hz and >0.98 at 0.10 Hz in both age groups. The OLBNP protocol conclusively revealed the cerebrovascular system functions as a high-pass filter during exercise throughout aging. It was also discovered that the older adults had elevations (+71%) in normalized gain (+0.46 ± 0.36%/%: 0.05 Hz) and reductions (-34%) in phase (-0.24 ± 0.22 radian: 0.10 Hz). There were also age-related phase differences between resting and exercise conditions. It is speculated that these age-related changes in the TFA metrics are mediated by alterations in vasoactive factors, sympathetic tone, or the mechanical buffering of the compliance vessels.

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Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline ( < 0.01), a finding explained by a lower [Formula: see text] ( < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline ( = 6) had no effect on CBF compared with placebo ( = 6) when end-tidal gases were comparable ( > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans. The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.

At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g., shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that ) at rest, SNA would be elevated and FMD would be reduced at HA compared with sea-level (SL); and) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344 m) and HA (5,050 m) in 14 participants during mild lower-body negative pressure (LBNP; -10 mmHg) and lower-body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrocardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants ( = 5). Our findings were ) at rest, SNA was elevated ( < 0.01), and absolute FMD was reduced ( = 0.024), but relative FMD remained unaltered ( = 0.061), at HA compared with SL; and ) despite significantly altering SNA with LBNP (+60.3 ± 25.5%) and LBPP (-37.2 ± 12.7%) ( < 0.01), FMD was unaltered at SL ( = 0.448) and HA ( = 0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA. The role of the sympathetic nervous system on endothelial function remains unclear. We used lower-body negative and positive pressure to manipulate sympathetic nervous activity at sea level and high altitude and measured brachial endothelial function via flow-mediated dilation. We found that acutely altering sympathetic nervous activity had no effect on endothelial function.