Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit.

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 (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.

Sympathetic activity is not a main cause of blood pressure reduction with exercise training in un-medicated middle-aged/older men.

BACKGROUND: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men. METHODS: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55 ± 3 years; n = 13) and normotensive controls (mean age 60 ± 5 years; n = 12) participated in 8 weeks of supervised high-intensity interval spinning training. Before and after training, muscle sympathetic nerve activity (MSNA) and blood pressure were measured at rest and during a sympatho-excitatory cold pressor test (CPT). Based on the measurements, baroreceptor sensitivity and baroreceptor threshold were calculated. RESULTS: Resting MSNA and baroreceptor sensitivity were similar for the hypertensive and the normotensive groups. Training lowered MSNA (p < 0.05), expressed as burst frequency (burst/min), overall, and to a similar extent, in both groups (17% and 27%, respectively, in hypertensive and normotensive group), whereas blood pressure was only significantly (p < 0.05) lowered (by 4 mmHg in both systolic and diastolic pressure) in the hypertensive group. Training did not (p > 0.05) alter the MSNA or blood pressure response to CPT or increase baroreceptor sensitivity but reduced (p < 0.05) the baroreceptor threshold with a main effect for both groups. Training adherence and intensity were similar in both groups yet absolute maximal oxygen uptake increased by 15% in the normotensive group only. CONCLUSION: The dissociation between the training induced changes in resting MSNA, lack of change in baroreflex sensitivity and the change in blood pressure, suggests that MSNA is not a main cause of the blood pressure reduction with exercise training in un-medicated middle-aged/older men.

Acute hypoxia elicits lasting reductions in the sympathetic action potential transduction of arterial blood pressure in males.

Post-hypoxia sympathoexcitation does not elicit corresponding changes in vascular tone, suggesting diminished sympathetic signalling. Blunted sympathetic transduction following acute hypoxia, however, has not been confirmed and the effects of hypoxia on the sympathetic transduction of mean arterial pressure (MAP) as a function of action potential (AP) activity is unknown. We hypothesized that MAP changes would be blunted during acute hypoxia but restored in recovery and asynchronous APs would elicit smaller MAP changes than synchronous APs. Seven healthy males (age: 24 (3) years; BMI: 25 (3) kg/m2 ) underwent 20 min isocapnic hypoxia (PET O2 : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 7 min) and late (last 7 min) recovery. AP groups were classified as synchronous APs, asynchronous APs (occurring outside an MSNA burst) and no AP activity. Sympathetic transduction of MAP was quantified using signal-averaging, with ΔMAP tracked following AP group cardiac cycles. Following synchronous APs, ΔMAP was reduced in hypoxia (+1.8 (0.9) mmHg) and early recovery (+1.5 (0.7) mmHg) compared with baseline (+3.1 (2.2) mmHg). AP group-by-condition interactions show that at rest asynchronous APs attenuate MAP reductions compared with no AP activity (-0.4 (1.1) vs. -2.2 (1.2) mmHg, respectively), with no difference between AP groups in hypoxia, early or late recovery. Sympathetic transduction of MAP is blunted in hypoxia and early recovery. At rest, asynchronous sympathetic APs contribute to neural regulation of MAP by attenuating nadir pressure responses. KEY POINTS: Acute isocapnic hypoxia elicits lasting sympathoexcitation that does not correspond to parallel changes in vascular tone, suggesting blunted sympathetic transduction. Signal-averaging techniques track the magnitude and temporal cardiovascular responses following integrated muscle sympathetic nerve activity (MSNA) burst and non-burst cardiac cycles. However, this does not fully characterize the effects of sympathetic action potential (AP) activity on blood pressure control. We show that hypoxia blunts the sympathetic transduction of mean arterial pressure (MAP) following synchronous APs that form integrated MSNA bursts and that sympathetic transduction of MAP remains attenuated into early recovery. At rest, asynchronous APs attenuate the reduction in MAP compared with cardiac cycles following no AP activity, thus asynchronous sympathetic APs appear to contribute to the neural regulation of blood pressure. The results advance our understanding of sympathetic transduction of arterial pressure during and following exposure to acute isocapnic hypoxia in humans.

Dietary Intake of Young Male Ice Hockey Players 10-13 Years of Age during a Week-Long Hockey Camp.

This study recorded the dietary intakes of young male ice hockey players (10-13 year (yr)) for 3 consecutive days while participating in a 5-day summer hockey camp. Players were categorized as older children (OC, n = 10; 10.7 ± 0.2 yr; 37.1 ± 1.5 kg; 147.9 ± 2.1 cm) and young adolescents (YA, n = 10; 12.9 ± 0.1 yr; 45.2 ± 1.5 kg; 157.0 ± 2.4 cm). Players consumed their usual daily intakes. Parents recorded food intake in the mornings and evenings, while the researchers recorded food intake at camp. Energy intake was higher in both groups when compared to data for age-matched young Canadian (CDN) males (OC, 2967 ± 211 vs. 2000 kcal/day; YA, 2773 ± 91 vs. 2250 kcal/day). Carbohydrate (CHO) (OC, 11.2 ± 0.8 vs. YO, 8.9 ± 0.5 g/kg body mass/day) and protein (OC, 3.2 ± 0.3; YO, 2.4 ± 0.1 g/kg/day) intakes were higher than reported for young CDN males (CHO, 3.6 and protein, 1.0 g/kg/day) and were within the Acceptable Macronutrient Distribution Range (AMDR; CHO, 56 ± 2.3; 57.4 ± 0.8%; protein, 16.1 ± 1.0; 15.7 ± 0.7%). Fat intake was also within the AMDR in both groups (OC, 29.8 ± 1.6%; YA, 28.3 ± 1.0%). Micronutrient intake was adequate except for Vitamin D intakes that were below the recommended 15 ug/day at 6.3 ± 0.7 (OC) and 5.0 ± 1.5 ug/day (YA). In summary, energy and macronutrient intakes of the OC (10-11 yr) and YA (12-13 yr) players were high and well above the age matched CDN norms. The older children had higher energy intakes/kg body mass than the young adolescents. Higher energy intakes allowed for micronutrients intakes to be met in these young active males, except for vitamin D intake.

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia-induced sympathetic long-term facilitation.

Baroreflex resetting permits sympathetic long-term facilitation (sLTF) following hypoxia; however, baroreflex control of action potential (AP) clusters and AP recruitment patterns facilitating sLTF is unknown. We hypothesized that baroreflex resetting of arterial pressure operating points (OPs) of AP clusters and recruitment of large-amplitude APs would mediate sLTF following hypoxia. Eight men (age: 24 (3) years; body mass index: 24 (3) kg/m2 ) underwent 20 min isocapnic hypoxia ( PETO2${P_{{\rm{ET}}{{\rm{O}}_{\rm{2}}}}}$ : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and a continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 5 min), and late recovery (last 5 min). AP amplitude (normalized to largest baseline AP amplitude), percentage APs occurring outside a MSNA burst (percentage asynchronous APs), and proportion of APs firing in small (1-3), medium (4-6) and large (7-10) normalized cluster sizes was calculated. Normalized clusters were used to assess baroreflex OPs and sensitivity. Hypoxia increased total MSNA activity, which remained elevated during recovery (P < 0.0001). Baroreflex OPs were shifted rightward for all clusters in recovery, with no effect on slope. Compared to baseline, AP amplitude was elevated by 3 (2)% and 4 (2)% while asynchronous APs were reduced by 9 (5)% and 7 (6)% in early and late recovery, respectively. In early recovery, the proportion of APs firing in large clusters was increased compared to baseline. Hypoxia-induced sLTF is mediated by baroreflex resetting of AP clusters to higher OPs, reduced asynchronous AP firing, and increased contribution from large-amplitude APs. KEY POINTS: Acute isocapnic hypoxia resets the arterial baroreflex and permits long-lasting sympathoexcitation, termed sympathetic long-term facilitation. Our understanding of sympathetic long-term facilitation following hypoxia in humans is based on multiunit muscle sympathetic nerve activity and does not fully characterize the underlying baroreflex control of sympathetic neuronal subpopulations or their discharge/recruitment strategies. We show that sympathetic long-term facilitation is mediated by baroreflex resetting of sympathetic action potential clusters to higher arterial pressure operating points, a reduction in the percentage of action potentials firing asynchronously, and a shift toward larger amplitude action potential activity. The results advance our fundamental understanding of how the sympathetic nervous system mediates sympathetic long-term facilitation following exposure to acute isocapnic hypoxia in humans.

The coronary vascular response to the metaboreflex at low altitude and during acute and prolonged high altitude in males.

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 paradoxical coronary vasoconstriction. Whether coronary blood velocity is reduced by metaboreflex activation following travel and/or adaptation to high altitude is unknown. This study determined if the response of the coronary vasculature to muscle metaboreflex activation at low altitude differs from acute (1/2 days) and prolonged (8/9 days) high altitude. Healthy males (n = 16) were recruited and performed isometric handgrip exercise (30% max) followed by postexercise circulatory occlusion (PECO) to isolate the muscle metaboreflex at low altitude and following acute and prolonged high altitude (3,800 m). Mean left anterior descending coronary artery blood velocity (LADvmean, transthoracic Doppler echocardiography), heart rate, mean arterial pressure (MAP), ventilation, and respired gases were assessed during baseline and PECO at all time points. Coronary vascular conductance index (CVCi) was calculated as LADVmean/MAP. The change in LADvmean (acute altitude: -1.7 ± 3.9 cm/s, low altitude: 2.6 ± 3.4 cm/s, P = 0.01) and CVCi (acute altitude: -0.05 ± 0.04 cm/s/mmHg, low altitude: -0.01 ± 0.03 cm/s/mmHg, P = 0.005) induced by PECO differed significantly between acute high altitude and low altitude. The change in LADVmean and CVCi induced by PECO following prolonged high altitude was not different from low altitude. Our results suggest that coronary vasoconstriction with metaboreflex activation in males is greatest following acute ascent to high-altitude and restored to low-altitude levels following 8-9 days of acclimatization.NEW & NOTEWORTHY Coronary blood flow is regulated by both local metabolic signaling pathways and adrenergic activity in healthy humans. The integrated effects of these systems on coronary vascular physiology are not well understood. Using Doppler echocardiography, this study demonstrates that adrenergic stimulation caused by metaboreflex activation leads to greater reductions in coronary vascular conductance following acute high-altitude but not after prolonged high-altitude exposure.

Sex differences in the coronary vascular response to combined chemoreflex and metaboreflex stimulation in healthy humans.

NEW FINDINGS: What is the central question of this study? Coronary blood flow in healthy humans is controlled by both local metabolic signalling and adrenergic activity: does the integration of these signals during acute hypoxia and adrenergic activation differ between sexes? What are the main findings and its importance? Both males and females exhibit an increase in coronary blood velocity in response to acute hypoxia, a response that is constrained by adrenergic stimulation in males but not females. These findings suggest that coronary blood flow control differs between males and females. ABSTRACT: Coronary hyperaemia is mediated through multiple signalling pathways, including local metabolic messengers and adrenergic stimulation. This study aimed to determine whether the coronary vascular response to adrenergic stressors is different between sexes in normoxia and hypoxia. Young, healthy participants (n = 32; 16F) underwent three randomized trials of isometric handgrip exercise followed by post-exercise circulatory occlusion (PECO) to activate the muscle metaboreflex. End-tidal PO2 was controlled at (1) normoxic levels throughout the trial, (2) 50 mmHg for the duration of the trial (hypoxia trial), or (3) 50 mmHg only during PECO (mixed trial). Mean left anterior descending coronary artery velocity (LADVmean ; transthoracic Doppler echocardiography), heart rate and blood pressure were assessed at baseline and during PECO. In normoxia, there was no change in LADVmean or cardiac workload induced by PECO in males and females. Acute hypoxia increased baseline LADVmean to a greater extent in males compared with females (P < 0.05), despite a similar increase in cardiac workload. The change in LADVmean induced by PECO was similar between sexes in normoxia (P = 0.31), greater in males during the mixed trial (male: 12.8 (7.7) cm/s vs. female: 8.1 (6.3) cm/s; P = 0.02) and reduced in males but not females in acute hypoxia (male: -4.8 (4.5) cm/s vs. female: 0.8 (6.2) cm/s; P = 0.006). In summary, sex differences in the coronary vasodilatory response to hypoxia were observed, and metaboreflex activation during hypoxia caused a paradoxical reduction in coronary blood velocity in males but not females.

Dietary Macronutrient and Micronutrient Intake over a 7-Day Period in Female Varsity Ice Hockey Players.

This study examined the energy, macronutrient, and micronutrient intakes of female ice hockey players over a 7-d period including game, practice, and rest days. Twenty-three female varsity players (19.0 ± 1.1 yr, 167.1 ± 6.5 cm, 67.0 ± 8.0 kg) volunteered for the study. Average total daily energy expenditure (TDEE) was estimated over the 7-day period. Average 7-day energy intake (EI) and TDEE were 2354 ± 353 and 2304 ± 204 kcal. The majority (n = 19) of athletes had an EI ≥ 90% of their estimated TDEE. Macronutrient intake was 52% carbohydrate (CHO), 32% fat, and 16% protein of total EI, although CHO intake was slightly below recommendations (5 g/kg BM/d) on game and practice (4.8 ± 1.4 and 4.5 g/kg BM/d) days. Game day EI was greater than practice and rest days. Recommended micronutrient intakes were not met by most athletes for iron, calcium, vitamin D, and potassium, and intakes were similar between game, practice, and rest days. In summary, the average EI for female varsity ice hockey players appeared adequate to meet their energy needs over a weekly cycle of game, practice, and rest days. However, these female athletes would benefit from increasing CHO intake on game and practice days and selecting foods that are rich in vitamins and minerals.

Muscle sympathetic single-unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: the role of sympathoexcitation magnitude.

A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy young males at baseline and during 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2 47 ± 3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA [Δ273 ± 208 vs. Δ254 ± 193 arbitrary units (AU), P = 0.84] and single-unit spike frequency (Δ8 ± 10 vs. Δ12 ± 13 spikes/min, P = 0.12). Among 19 identified single units, the proportions of activated (47% vs. 68%), nonresponsive (32% vs. 16%), and inhibited (21% vs. 16%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P = 0.42). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (7 activated, 1 nonresponsive, and 1 inhibited during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (Δ595 ± 282 AU, P < 0.01) only one single unit was inhibited. These findings suggest that the proportions of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.NEW & NOTEWORTHY Subpopulations of muscle sympathetic single units can be inhibited during mild sympathoexcitatory stress. We demonstrate that rhythmic handgrip exercise and isocapnic hypoxia, when matched by multiunit sympathoexcitation, induce similar proportions of single-unit inhibition, highlighting that heterogeneous single-unit response patterns are related to the level of sympathoexcitation independent of the stressor type. Interestingly, only 47% of single units behaved with concordant response patterns between stressors, suggesting the potential for functional specificity within the postganglionic neuronal pool.

Vasodilatation by carbon dioxide and sodium nitroglycerin reduces compliance of the cerebral arteries in humans.

NEW FINDINGS: What is the central question of this study? Vascular compliance importantly contributes to the regulation of cerebral perfusion and complex mechanisms are known to influence compliance of a vascular bed: while vasodilatation mediates changes in vascular resistance, does it also affect compliance, particularly in the cerebral vasculature? What is the main finding and its importance? Cerebral vasodilatation, elicited by hypercapnia and sodium nitroglycerin administration, reduced cerebrovascular compliance by approximately 26% from baseline. This study provides new insight into mechanisms mediating cerebrovascular compliance. ABSTRACT: Changes in vascular resistance and vascular compliance contribute to the regulation of cerebral perfusion. While changes in vascular resistance are known to be mediated by vasodilatation, the mechanisms contributing to changes in vascular compliance are complex. In particular, whether vasodilatation affects compliance of the vasculature within the cranium remains unknown. Therefore, the present study examined the impact of two vasodilatation pathways on cerebrovascular compliance in humans. Fifteen young, healthy adults (26 ± 5 years, seven females) completed two protocols: (i) sublingual sodium nitroglycerin (SNG; 0.4 mg) and (ii) hypercapnia (5-6% carbon dioxide gas mixture for 4 min). Blood pressure waveforms (finger photoplethysmography) and middle cerebral artery blood velocity waveforms (transcranial Doppler ultrasound) were input into a modified Windkessel model and an index of cerebrovascular compliance (Ci) was calculated. During the SNG protocol, Ci decreased 24 ± 17% from baseline ((5.0 ± 2.3) × 10-4  cm s-1  mmHg-1 ) to minute 10 ((3.6 ± 1.2) × 10-4  cm s-1  mmHg-1 ; P = 0.009). During the hypercapnia protocol, Ci decreased 28 ± 9% from baseline ((4.4 ± 1.9) × 10-4  cm s-1  mmHg-1 ) to minute 4 ((3.1 ± 1.4) × 10-4  cm s-1  mmHg-1 ; P < 0.001). Cerebral vasodilatory stimuli induced by nitric oxide and carbon dioxide mechanisms reduced compliance of the cerebral vascular bed by approximately 26% from supine baseline values.

Muscle Metaboreflex Control of Sympathetic Activity Is Preserved after Acute Intermittent Hypercapnic Hypoxia.

PURPOSE: In normotensive patients with obstructive sleep apnea (OSA), the muscle sympathetic nerve activity (MSNA) response to exercise is increased while metaboreflex control of MSNA is decreased. We tested the hypotheses that acute intermittent hypercapnic hypoxia (IHH) in males free from OSA and associated comorbidities would augment the MSNA response to exercise but attenuate the change in MSNA during metaboreflex activation. METHODS: Thirteen healthy males (age = 24 ± 4 yr) were exposed to 40 min of IHH. Before and after IHH, the pressor response to exercise was studied during 2 min of isometric handgrip exercise (at 30% maximal voluntary contraction), whereas the metaboreflex was studied during 4 min of postexercise circulatory occlusion (PECO). Mean arterial pressure (MAP), heart rate (HR), and fibular MSNA were recorded continuously. MSNA was quantified as burst frequency (BF) and total activity (TA). Mixed effects linear models were used to compare the exercise pressor and metaboreflex before and after IHH. RESULTS: As expected, IHH led to significant increases in MSNA BF, TA, and MAP at baseline and throughout exercise and PECO. However, during handgrip exercise, the change from baseline in MAP, HR, MSNA BF, and TA was similar before and after IHH (All P > 0.31). During PECO, the change from baseline in MSNA BF and TA was similar after IHH, whereas the change from baseline in MAP (Δ14 mm Hg, 95% CI = 7-19, vs Δ16 mm Hg, 95% CI = 10-21; P < 0.01) was modestly increased. CONCLUSION: After acute IHH, MSNA response to handgrip exercise and metaboreflex activation were preserved in healthy young males despite overall increases in resting MSNA and MAP. Chronic IHH and comorbidities often associated with OSA may be required to modulate the exercise pressor reflex and metaboreflex.

Influence of blood Po2 on the stability of agitated saline contrast.

The utility of transthoracic saline contrast echocardiography (TTSCE) to assess blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) in humans is limited due to the potential destabilizing effects of the gas concentration gradients established in varied blood-gas environments. This study assessed the specific effect of a hyperoxic and mixed venous blood-gas environment on the stability of saline contrast. We hypothesized that the rate of contrast mass lost in hyperoxic blood would be similar to mixed venous due to the establishment of equal and opposing gas gradients (O2, N2, CO2) created when the partial pressure of dissolved gases is manipulated. Using an in vitro model of the pulmonary circulation perfused with defibrinated sheep blood and a membrane oxygenator to control blood gases, we assessed the percent contrast conserved (an index of contrast stability) between inflow and outflow sites at multiple flow rates (1.8, 2.8, 4.3, and 6.8 L/min) in a hyperoxic (Po2: 646 ± 16 mmHg; Pco2: 0 ± 0 mmHg) and a mixed venous blood gas condition (Po2: 35 ± 3 mmHg; Pco2: 40 ± 0 mmHg). We found significant contrast decay with time in both conditions, with slightly higher contrast conservation in the hyperoxia trials (64 ± 32%) versus the mixed venous trials (55 ± 21%). These findings suggest that contrast stability is not likely a factor affecting the interpretation of TTSCE performed in healthy humans breathing hyperoxia and lends support to the existence of a local O2-dependent mechanism contributing to the regulation of Q̇IPAVA.NEW & NOTEWORTHY Hyperoxic blood has a small stabilizing effect on agitated saline contrast compared with mixed venous blood, lending support to studies that show the reversal of exercise-induced blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) with hyperoxia. These data support the possible presence of a local O2-dependent regulatory mechanism within the pulmonary vasculature that may play a role in Q̇IPAVA regulation.

Acute intermittent hypercapnic hypoxia and cerebral neurovascular coupling in males and females.

The decline in cognition observed in obstructive sleep apnea is linked to intermittent hypercapnic hypoxia (IHH), which is known to impair cerebrovascular reactivity. Whether acute IHH impairs the matching of cerebral blood flow to metabolism (i.e., neurovascular coupling, NVC) is unknown. We hypothesized that acute IHH would reduce cerebral NVC. Healthy participants (N = 17, 8 females, 9 males; age: 22 ± 3 years) had cerebral NVC measured at baseline and following 40-min of IHH at 1-min cycles with 40-s of hypercapnic hypoxia (target PETO2 = 50 mmHg, PETCO2 = +4 mmHg above baseline) and 20-s of normoxia. Cerebral NVC was quantified as the absolute and relative posterior cerebral artery blood velocity (PCAV; transcranial Doppler) and conductance (PCACVC; PCAV/mean arterial pressure [MAP]) response to a visual stimulus paradigm. Following IHH, resting PCAV was unchanged, MAP increased (+4 ± 6 mmHg, P < 0.01) and PCACVC was reduced (-0.05 ± 0.04 cm/s/mmHg, P < 0.01). The peak PCAV response to visual stimuli was unchanged following IHH, but the absolute and relative peak PCACVC response was increased (+0.011 ± 0.019 cm/s/mmHg, P < 0.05 and +4.8 ± 6.1%, P < 0.01, respectively) suggesting an increased cerebral vasodilatory response. No change occurred in the plateau cerebral NVC response following IHH. Changes in resting MAP induced by IHH did not correlate with changes in relative peak PCACVC (r2 = 0.095, P = 0.23). Cerebral NVC did not differ between sexes across all time points and was unchanged following a time-matched air-breathing control. In summary, acute IHH increases peak but not plateau cerebral NVC potentially through IHH mediated neuroplasticity.

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. ABSTRACT: The impact of oxygen on the circulatory responses to a cold pressor test (CPT) in lowlanders and Andean highlanders remains unknown. Our hypotheses were as follows: (i) in lowlanders, acute normobaric and hypobaric hypoxia would attenuate the common carotid artery (CCA) diameter response to the CPT compared with normobaric normoxia; (ii) Andean highlanders would exhibit a greater CCA diameter response compared with lowlanders; and (iii) a positive relationship between CCA diameter and blood pressure in response to the CPT would be present in both lowlanders and highlanders. Healthy lowlanders (n = 13) and Andean highlanders (n = 8) were recruited and conducted an isocapnic CPT, which consisted of a 3 min foot immersion into water at 0-1°C. Blood pressure (finger photoplethysmography) and CCA diameter and blood flow (Duplex ultrasound) were recorded continuously. The CPT was conducted in lowlanders at sea level in isocapnic normoxic and hypoxic conditions and after 10 days of acclimatization to 4300 m (Cerro de Pasco, Peru) in hypoxic and hyperoxic conditions. Andean highlanders were tested at rest at high altitude. The main findings were as follows: (i) in lowlanders, normobaric but not hypobaric hypoxia elevated CCA reactivity to the CPT; (ii) no differences in response to the CPT were observed between lowlanders and highlanders; and (iii) although hypobaric hypoxaemia reduced the relationship between CCA diameter and blood pressure compared with normobaric normoxia (P = 0.132), hypobaric hyperoxia improved this relationship (P = 0.012), and no relationship was observed in Andean highlanders (P = 0.261). These data demonstrate that the circulatory responses to a CPT were modified by oxygen in lowlanders, but were unaltered with lifelong hypoxic exposure.

Peripheral chemoreflex contribution to ventilatory long-term facilitation induced by acute intermittent hypercapnic hypoxia in males and females.

KEY POINTS: Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that develops following intermittent hypoxia in both healthy and clinical populations. A sustained hypercapnic background is argued to be required for full vLTF expression in humans. We determined whether acute intermittent hypercapnic hypoxia elicits vLTF during isocapnic-normoxic recovery in healthy males and females. We further assessed whether tonic peripheral chemoreflex drive is necessary and contributes to the expression of vLTF. Following 40 min of intermittent hypercapnic hypoxia, minute ventilation was increased throughout 50 min of isocapnic-normoxic recovery. Inhibition of peripheral chemoreflex drive with hyperoxia attenuated the magnitude of vLTF. Males and females achieve vLTF through different respiratory recruitment patterns. ABSTRACT: Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that manifests as increased minute ventilation ( V̇I ) following intermittent hypoxia. In humans, hypercapnia sustained throughout intermittent hypoxia and recovery is considered necessary for vLTF expression. We examined whether acute intermittent hypercapnic hypoxia (IHH) induces vLTF, and if peripheral chemoreflex drive contributes to vLTF throughout isocapnic-normoxic recovery. In 19 individuals (9 females, age: 22 ± 3 years; mean ± SD), measurements of tidal volume (VT ), breathing frequency (fB ), V̇I , and end-tidal gases ( PETO2 and PETCO2 ), were made at baseline, during IHH and 50 min of recovery. Totalling 40 min, IHH included 1 min intervals of 40 s hypercapnic hypoxia (target PETO2  = 50 mmHg and PETCO2  = +4 mmHg above baseline) and 20 s normoxia. During baseline and recovery, dynamic end-tidal forcing maintained resting PETO2 and PETCO2 and delivered 1 min of hyperoxia ( PETO2  = 355 ± 7 mmHg) every 5 min. The depression in V̇I during hyperoxia was considered an index of peripheral chemoreflex drive. Throughout recovery V̇I was increased 4.6 ± 3.7 l min-1 from baseline (P < 0.01). Hyperoxia depressed V̇I at baseline, and augmented depression was evident following IHH (Δ V̇I  = -0.8 ± 0.9 vs. -1.7 ± 1.3 l min-1 , respectively, P < 0.01). The vLTF was similar between sexes (P = 0.15), but males had larger increases in VT than females (sex-by-time interaction, P = 0.03), and females tended to increase fB (P = 0.09). During isocapnic-normoxic recovery following IHH: (1) vLTF is expressed in healthy humans; (2) vLTF expression is attenuated but not abolished with peripheral chemoreflex inhibition by hyperoxia, suggesting a contribution from central nervous pathways in vLTF expression; and (3) males and females develop similar vLTF through different ventilatory recruitment strategies.

Case Studies in Physiology: Sympathetic neural discharge patterns in a healthy young male during end-expiratory breath hold-induced sinus pause.

This case study reports the efferent muscle sympathetic nerve activity (MSNA) discharge patterns during a sinus pause observed during a maximal end-expiratory apnea in a young healthy male (age = 26 yr). During a 15.3-s end-expiratory apnea following a bout of intermittent hypercapnic hypoxia, we observed a 5.2-s (R-R interval) sinus pause and integrated MSNA recording, demonstrating a square-wave discharge pattern atypical of sharp MSNA burst peaks entrained to cardiac cycles or during preventricular contractions. This abnormal MSNA discharge pattern was observed again during a follow-up experiment, where an end-expiratory apnea at baseline resulted in pronounced bradycardia (R-R intervals >2.5-s) but failed to reproduce the 5.2-s sinus pause. Action potential (AP) discharge patterns during MSNA bursts were detected using a continuous wavelet transform approach. AP discharge increased by 300% during the end-expiratory apnea with 5.2-s sinus pause compared with baseline and involved increased firing (i.e., rate-coding) of AP clusters (bins of AP with similar morphology) already present during baseline and pronounced recruitment of larger-amplitude AP clusters not present at baseline. Large-amplitude AP clusters continued to discharge during sinus pause. In summary, we show MSNA discharge during sinus pause and pronounced bradycardia during end-expiratory apnea, which demonstrates a square-wave discharge with recruitment of latent larger-amplitude AP clusters. The MSNA discharge was terminated before systole following sinus pause potentially through an inhibitory influence of inspiration, or cardiac mechanoreceptor feedback causing burst termination.NEW & NOTEWORTHY We characterize the occurrence of a square-wave discharge pattern of efferent muscle sympathetic nerve activity during a sinus pause in a young healthy male. This discharge pattern comprised large recruited action potential clusters undetected at baseline that continuously discharged during the sinus pause. Notably, this discharge pattern was still contained within a single cardiac cycle.

Within-breath sympathetic baroreflex sensitivity is modulated by lung volume but unaffected by acute intermittent hypercapnic hypoxia in men.

Muscle sympathetic nerve activity (MSNA) exhibits well-described within-breath respiratory modulation, but the interactive contributions of the arterial baroreflex remain unclear. The present study assessed 1) within-breath modulation of sympathetic baroreflex sensitivity (BRS) and 2) the effect of acute intermittent hypercapnic hypoxia (IHH) on within-breath sympathetic BRS and respiratory-sympathetic entrainment. Seventeen men (24 ± 4 yr) underwent an 8- to 10-min spontaneously breathing baseline while continuous measures of blood pressure (BP), heart rate, MSNA, ventilation, and end-tidal gases were collected. A subset of 12 participants subsequently underwent a 40-min IHH exposure composed of 40 consecutive 1-min breathing cycles: 40 s of hypercapnic hypoxia and 20 s of normoxia. Data were compared between inspiration and expiration and low and high lung volume (calculated from the integral of spirometry-derived flow). Sympathetic BRS was determined by the slope of the weighted linear regression between diastolic BP and MSNA burst incidence. Respiratory-sympathetic entrainment was quantified as percentage of MSNA bursts during each respiratory epoch relative to the total burst count. Sympathetic BRS was similar between inspiration and expiration (-3.9 ± 2.0 vs. -3.6 ± 1.8 bursts·100 heartbeats-1·mmHg-1; P = 0.61) but greater during low versus high lung volumes (-4.6 ± 2.3 vs. -2.1 ± 1.6 bursts·100 heartbeats-1·mmHg-1; P < 0.01). High (r = -0.64; P < 0.01)- but not low (r = -0.24; P = 0.35)-lung volume sympathetic BRS was associated with resting MSNA. IHH increased resting MSNA burst frequency (15 ± 7 vs. 20 ± 7 bursts/min; P < 0.01) and diastolic BP (68 ± 5 vs. 77 ± 9 mmHg; P = 0.02), without altering resting or within-breath sympathetic BRS or respiratory-sympathetic entrainment (all P > 0.05). These findings provide novel insight into the mechanisms controlling within-breath modulation of sympathetic outflow in humans.NEW & NOTEWORTHY In resting spontaneously breathing men, the present study observed that sympathetic baroreflex sensitivity (BRS) was higher during low versus high lung volumes but not different between inspiration and expiration. High- but not low-lung volume BRS was negatively associated with resting muscle sympathetic nerve activity (MSNA). Acute intermittent hypercapnic hypoxia increased resting MSNA and diastolic blood pressure, without altering within-breath BRS. These findings provide novel insight into mechanisms controlling within-breath modulation of MSNA in humans.

Angiotensin II-Type I Receptor Antagonism Does Not Influence the Chemoreceptor Reflex or Hypoxia-Induced Central Sleep Apnea in Men.

Components of the renin-angiotensin system (RAS) situated within the carotid body or central nervous system may promote hypoxia-induced chemoreceptor reflex sensitization or central sleep apnea (CSA). We determined if losartan, an angiotensin-II type-I receptor (AT1R) antagonist, would attenuate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia, and consequently CSA severity. In a double-blind, randomized, placebo-controlled, crossover protocol, 14 men (age: 25 ± 2 years; BMI: 24.6 ± 1.1 kg/m2; means ± SEM) ingested 3 doses of either losartan (50 mg) or placebo every 8 h. Chemoreceptor reflex sensitivity was assessed during hypoxic and hyperoxic hypercapnic ventilatory response (HCVR) tests and during six-20s hypoxic apneas before and after 8 h of sleep in normobaric hypoxia (F I O2 = 0.135). Loop gain was assessed from a ventilatory control model fitted to the ventilatory pattern of CSA recorded during polysomnography. Prior to nocturnal hypoxia, losartan had no effect on either the hyperoxic (losartan: 3.6 ± 1.1, placebo: 4.0 ± 0.6 l/min/mmHg; P = 0.9) or hypoxic HCVR (losartan: 5.3 ± 1.4, placebo: 5.7 ± 0.68 l/min/mmHg; P = 1.0). Likewise, losartan did not influence either the hyperoxic (losartan: 4.2 ± 1.3, placebo: 3.8 ± 1.1 l/min/mmHg; P = 0.5) or hypoxic HCVR (losartan: 6.6 ± 1.8, placebo: 6.3 ± 1.5 l/min/mmHg; P = 0.9) after nocturnal hypoxia. Cardiorespiratory responses to apnea and participants' apnea hypopnea indexes during placebo and losartan were similar (73 ± 15 vs. 75 ± 14 events/h; P = 0.9). Loop gain, which correlated with CSA severity (r = 0.94, P < 0.001), was similar between treatments. In summary, in young healthy men, hypoxia-induced CSA severity is strongly associated with loop gain, but the AT1R does not modulate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia.

Impairment of Thermoregulation and Performance via Mild Dehydration in Ice Hockey Goaltenders.

During play, ice hockey goaltenders routinely dehydrate through sweating and lose ≥2% body mass, which may impair thermoregulation and performance. PURPOSE: This randomized, crossover study examined the effects of mild dehydration on goaltender on-ice thermoregulation, heart rate, fatigue, and performance. METHODS: Eleven goaltenders played a 70-minute scrimmage followed by a shootout and drills to analyze reaction time and movements. On ice, they either consumed no fluid (NF) and lost 2.4% (0.3%) body mass or maintained body mass with water (WAT) or a carbohydrate-electrolyte solution (CES). Save percentage, rating of perceived exertion, heart rate, and core temperature were recorded throughout, and a postskate questionnaire assessed perceived fatigue. RESULTS: Relative to NF, intake of both fluids decreased heart rate (interaction: P = .03), core temperature (peak NF = 39.0°C [0.1°C], WAT = 38.6°C [0.1°C], and CES = 38.5°C [0.1°C]; P = .005), and rating of perceived exertion in the scrimmage (post hoc: P < .04), as well as increasing save percentage in the final 10 minutes of scrimmage (NF = 75.8% [1.9%], WAT = 81.7% [2.3%], and CES = 81.3% [2.3%], post hoc: P < .04). In drills, movement speed (post hoc: P < .05) and reaction time (post hoc: P < .04) were slower in the NF versus both fluid conditions. Intake of either fluid similarly reduced postskate questionnaire scores (condition: P < .0001). Only CES significantly reduced rating of perceived exertion in drills (post hoc: P < .05) and increased peak movement power versus NF (post hoc: P = .02). Shootout save percentage was similar between conditions (P = .37). CONCLUSIONS: Mild dehydration increased physiological strain and fatigue and decreased ice hockey goaltender performance versus maintaining hydration. Also, maintaining hydration with a CES versus WAT may further reduce perceived fatigue and positively affect movements.