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Intense inspiratory muscle work evokes a sympathetically mediated pressor reflex, termed the respiratory muscle metaboreflex, in which young females demonstrate an attenuated response relative to males. However, the effects of ageing and female sex hormones on the respiratory muscle metaboreflex are unclear. We tested the hypothesis that the pressor response to inspiratory work would be similar between older males and females, and higher relative to their younger counterparts. Healthy, normotensive young (26 ± 3 years) males (YM; n = 10) and females (YF; n = 10), as well as older (64 ± 5 years) males (OM; n = 10) and females (OF; n = 10), performed inspiratory pressure threshold loading (PTL) to task failure. Older adults had a greater mean arterial pressure (MAP) response to PTL than young (P < 0.001). YF had a lower MAP compared to YM (+10 ± 6 vs. +19 ± 15 mmHg, P = 0.026); however, there was no difference observed between OF and OM (+26 ± 11 vs. +27 ± 11 mmHg, P = 0.162). Older adults had a lower heart rate response to PTL than young (P = 0.002). There was no effect of sex between young females and males (+19 ± 9 and +27 ± 11 bpm, P = 0.186) or older females and males (+17 ± 7 and +20 ± 7 bpm, P = 0.753). We conclude the respiratory muscle metaboreflex response is heightened in older adults, and the sex effect between older males and post-menopause females is absent, suggesting an effect of circulating sex hormones. KEY POINTS: The arterial blood pressure response to the respiratory muscle metaboreflex is greater in older males and females. Compared to sex-matched young individuals, there is no sex differences in the blood pressure response between older males and post-menopause females. Our results suggest the differences between males and females in the cardiovascular response to high levels of inspiratory muscle work is abolished with reduced circulating female sex hormones., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

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/m 2 ) underwent 20 min isocapnic hypoxia (P ET O 2 : 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., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Cervical spinal cord injury (C-SCI) negatively impacts cardiac and respiratory function. As the heart and lungs are linked via the pulmonary circuit these systems are interdependent. Here, we utilized inspiratory and expiratory loading to assess whether augmenting the respiratory pump improves left-ventricular (LV) filling and output in individuals with motor-complete C-SCI. We hypothesized LV end-diastolic volume (LVEDV) would increase and decrease with inspiratory and expiratory loading, respectively. Participants (C-SCI: 7M/1F, 35 ± 7 years; able-bodied: 7M/1F, 32 ± 6 years) were assessed under five conditions during 45° head-up tilt; unloaded, inspiratory loading with -10 and -20 cmH 2 O oesophageal pressure (P oes ) on inspiration, and expiratory loading with +10 and +20 cmH 2 O P oes on expiration. An oesophageal balloon catheter monitored P oes , and LV structure and function were assessed by echocardiography. In C-SCI only, (1) +20 cmH 2 O reduced LVEDV vs. unloaded (81 ± 15 vs. 88 ± 11 ml, P = 0.006); (2) heart rate was higher during +20 cmH 2 O compared to unloaded (P = 0.001) and +10 cmH 2 O (P = 0.002); (3) cardiac output was higher during +20 cmH 2 O than unloaded (P = 0.002); and (4) end-expiratory lung volume was higher during +20 cmH 2 O vs. unloaded (63 ± 10 vs. 55 ± 13% total lung capacity, P = 0.003) but was unaffected by inspiratory loading. In both groups, -10 and -20 cmH 2 O had no significant effect on LVEDV. These findings suggest greater expiratory positive pressure acutely impairs LV filling in C-SCI, potentially via impaired venous return, mediastinal constraint and/or direct ventricular interaction subsequent to dynamic hyperinflation. Inspiratory loading did not significantly improve LV function in C-SCI and neither inspiratory nor expiratory loading affected cardiac function or lung volumes in able-bodied participants. KEY POINTS: Cervical spinal cord injury (C-SCI) alters both the cardiac and the respiratory system, but little is known about how these systems interact following injury. Here, we manipulated inspiratory or expiratory intrathoracic pressure (ITP) to mechanistically test the role of the respiratory pump in circulatory function in highly trained individuals with C-SCI and an able-bodied reference group. In individuals with C-SCI, greater ITP during expiratory loading caused dynamic hyperinflation that was associated with impaired left-ventricular filling. More negative ITP during inspiratory loading did not significantly alter left-ventricular volumes in either group. Interventions that prevent dynamic hyperinflation and/or enhance the ability to generate expiratory pressures may help preserve left-ventricular filling in individuals with C-SCI., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Key Points: Under normoxic conditions, both healthy female and male diaphragms fatigue at a similar degree when matched for absolute diaphragmatic work during inspiratory loading. We investigated whether similarities in diaphragm fatigability persist under acute hypoxic conditions. We found that, in acute hypoxia, fatigue of the diaphragm is greater in women compared to men, whereas the magnitude of fatigue in normoxia did not differ between sexes. When matched for maximal diaphragm strength, women and men had a similar pressor response to work-matched inspiratory loading, independent of oxygen availability., Abstract: In normoxia, women and men display a comparable magnitude of diaphragmatic fatigue (DF) after work-matched inspiratory loading. Whether these sex similarities are maintained under acute hypoxic conditions is unknown. We investigated the influence of acute hypoxia during work-matched inspiratory pressure-threshold loading (PTL) on DF in healthy women (n = 8) and men (n = 8). Two 5 min isocapnic PTL tasks targeting a transdiaphragmatic pressure (P di ) of 92 cmH 2 O in normoxia and hypoxia (8% O 2 ) were performed on separate days (≥48 h). DF was quantified by twitch P di (P di,tw ) via cervical magnetic stimulation post-PTL. Women and men had similar maximal P di (P di,max ; women: 171 ± 16, men: 178 ± 20 cmH 2 O) and relative target workload (women: 54 ± 5%, men: 53 ± 6% P di,max ). The absolute cumulative diaphragmatic work did not differ between sexes in normoxia (women: 12,653 ± 1796 cmH 2 O s -1 , men: 13,717 ± 1231 cmH 2 O s -1 ; P = 0.202) or hypoxia (women: 11,624 ± 1860 cmH 2 O s -1 , men: 12 722 ± 1502 cmH 2 O s -1 ; P = 0.189). In normoxia, the magnitude of reduction in P di,tw post-PTL was similar between sexes (women: -21.1 ± 8.4%, men: -22.5 ± 4.9 %; P = 0.193); however, a higher degree of DF was observed in women compared to men following PTL in acute hypoxia (women: -27.6 ± 7.7%, men: -23.4 ± 9.6%, P = 0.019). We conclude that the female diaphragm is more susceptible to fatigue after inspiratory loading under acute hypoxic conditions. This finding may be related to sex differences in diaphragm muscle metabolism, such as fibre type composition, contractile properties, substrate utilisation and blood perfusion., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: Diaphragm fatigue may increase the intensity (sensory dimension) and unpleasantness (affective dimension) of dyspnoea, which may partially explain why diaphragm fatigue negatively affects exercise performance. We hypothesized that diaphragm fatigue would negatively affect exercise performance via increases in both the intensity and unpleasantness of dyspnoea, and that the increase in dyspnoea would be mechanistically linked to an increase in diaphragmatic EMG (EMG di ), a surrogate measure of neural respiratory drive. Fatiguing the diaphragm prior to exercise reduced cycling performance and increased both the intensity and unpleasantness of dyspnoea. The change in submaximal dyspnoea unpleasantness was significantly correlated with the change in cycling performance. Pre-fatigue of the diaphragm did not increase EMG di during exercise and is therefore unrelated to the increase in either the sensory or affective dimension of exertional dyspnoea., Abstract: The purpose of this study was to examine the effect of diaphragm fatigue on the multidimensional components of dyspnoea and diaphragm electromyography (EMG di ) during cycling. Sixteen healthy males (age = 27 ± 5 yr, V ̇ O 2 max  = 45.8 ± 9.8 ml kg -1  min -1 ) completed two high-intensity, time-to-exhaustion cycling tests in randomized order: (i) inspiratory pressure threshold loading (PTL) prior to exercise to induce diaphragm fatigue (pre-DF) and (ii) no PTL (control). Diaphragm fatigue after PTL was confirmed via cervical magnetic stimulation of the phrenic nerves. Dyspnoea intensity and unpleasantness were measured throughout exercise with the 0-10 category-ratio Borg scale and following exercise using the Multidimensional Dyspnoea Profile (MDP). EMG di was continuously recorded via a multipair oesophageal electrode catheter. Time-to-exhaustion decreased with pre-DF vs. control (9.0 ± 5.5 vs. 10.7 ± 7.5 min, P = 0.023). Pre-DF increased dyspnoea intensity ratings by 0.6 ± 1.0 Borg 0-10 units at the highest equivalent submaximal exercise time (HESET) a participant could achieve in both conditions (P = 0.020). Dyspnoea unpleasantness ratings increased with pre-DF by 0.5 ± 1.0, 0.7 ± 1.2 and 0.9 ± 1.4 (all P < 0.05) Borg 0-10 units during the 2nd, 3rd and 4th minutes of exercise, respectively. There was a significant correlation between the change in breathing unpleasantness ratings at HESET and the change in time-to-exhaustion (r = 0.66, P = 0.006). The immediate perception domain, a combination of peak unpleasantness and specific dyspnoea descriptor intensity ratings, was the only component of the MDP that was significantly increased with pre-DF (4.3 ± 1.9 vs. 3.6 ± 1.8, P = 0.04). There were no significant differences in EMG di . In conclusion, diaphragm fatigue has negative effects on multiple domains of dyspnoea, which may partially explain why exercise performance decreases with it., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: The female diaphragm fatigues at a slower rate compared to that of males, with blunted cardiovascular consequences (i.e. inspiratory muscle metaboreflex). It is unclear if these findings are a function of relative or absolute diaphragmatic work. We asked if sex differences in diaphragm fatigue and the inspiratory muscle metaboreflex persisted during inspiratory loading performed at equal absolute intensities. We found that matching men and women for absolute diaphragmatic work resulted in an equal degree of diaphragm fatigue, despite women performing significantly greater work relative to body mass. Metabolite-induced reflex influences in sympathetic outflow originating from the diaphragm are attenuated in women, with potential implications for blood flow distribution during exercise., Abstract: In response to inspiratory pressure-threshold loading (PTL), women have greater inspiratory muscle endurance time, slower rate of diaphragm fatigue development, and a blunted pressor response compared to men. It is unclear if these differences are due to discrepancies in absolute diaphragm force output. We tested the hypothesis that following inspirations performed at equal absolute intensities, females would develop a similar level of diaphragm fatigue and an attenuated cardiovascular response relative to men. Healthy young men (n = 8, age = 24 ± 3 years) and women (n = 8, age = 23 ± 3 years) performed PTL whilst targeting a transdiaphragmatic pressure (P di ) of 92 cmH 2 O for 5 min. Diaphragm fatigue was assessed via twitch P di (P di,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial blood pressure were monitored continuously. During PTL, the absolute amount of diaphragm work was not different between men (13,399 ± 2019 cmH 2 O s) and women (12,986 ± 1846 cmH 2 O s; P > 0.05); however, women performed the PTL task at a higher relative P ¯ di /P di,max . Following inspiratory PTL, the magnitude of reduction in P di,tw was similar between men (-27.1 ± 7.2%) and women (-23.8 ± 13.8%; P > 0.05). There were significant increases in HR over time (P < 0.05), but this did not differ on the basis of sex (P > 0.05). Mean arterial blood pressure increased significantly over time in both men and women (P < 0.05); however, the rate of change was higher in men (6.24 ± 2.54 mmHg min -1 ) than in women (4.15 ± 2.52 mmHg min -1 ) (P < 0.05). We conclude that the female diaphragm is protected against severe fatigue when inspiratory work is excessive and as a result does not evoke overt sympathoexcitation., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Key Points: The effect of combined inspiratory and expiratory muscle training on resting and reflexive cardiac function, as well as exercise capacity, in individuals with cervical spinal cord injury (SCI) is presently unknown. Six weeks of combined inspiratory and expiratory muscle training enhances both inspiratory and expiratory muscle strength in highly-trained athletes with cervical SCI with no significant effect on lung function. There was a significant decrease in left-ventricular filling and stroke volume at rest in response to 45° head-up tilt, which is irreversible by respiratory muscle training. Combined inspiratory and expiratory muscle training increased peak aerobic work rate and reduced end-expiratory lung volumes during exercise, which may have implications for left-ventricular filling during exercise., Abstract: To investigate the pulmonary, cardiovascular and exercise responses to combined inspiratory and expiratory respiratory muscle training (RMT) in athletes with tetraplegia, six wheelchair rugby athletes (five males and one female, aged 33 ± 5 years) completed 6 weeks of pressure threshold RMT, 2 sessions day -1 on 5 days week -1 . Resting pulmonary and cardiac function, exercise capacity, exercising lung volumes and field-based exercise performance were assessed at pre-RMT, post-RMT and after a 6-week no RMT period. RMT enhanced maximal inspiratory (pre- vs. post-RMT: -76 ± 15 to -106 ± 23 cmH 2 O, P = 0.002) and expiratory (59 ± 26 to 73 ± 32 cmH 2 O, P = 0.007) mouth pressures, as well as peak expiratory flow (6.74 ± 1.51 vs. 7.32 ± 1.60 L/s, P < 0.04). Compared to pre-RMT, peak work rate was higher at post-RMT (60 ± 23 to 68 ± 22 W, P = 0.003), whereas exercising end-expiratory lung volumes were reduced (P < 0.017). Peak oxygen uptake increased in all athletes at post-RMT (1.24 ± 0.40 vs. 1.40 ± 0.50 l min -1 , P = 0.12). After 6 weeks of no RMT all indices returned towards baseline, with peak work rate (P = 0.037), peak oxygen uptake (P = 0.041) and end-expiratory lung volume (P < 0.034) being significantly lower at follow-up than at post-RMT. There was a significant decrease in left-ventricular end-diastolic volume and stroke volume in response to 45° head-up tilt (P = 0.030 and 0.021, respectively); however, all cardiac indices in both supine and tilted positions were unchanged by RMT. Our findings demonstrate the efficacy of RMT with respect to enhancing respiratory muscle strength, lowering exercising lung volumes and increasing exercise capacity. Although the precise mechanisms by which RMT may enhance exercise capacity remain unclear, our data suggest that it is probably not the result of a direct cardiac adaptation associated with RMT., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Key Points: The perceived intensity of exertional breathlessness (i.e. dyspnoea) is higher in older women than in older men, possibly as a result of sex-differences in respiratory system morphology. During exercise at a given absolute intensity or minute ventilation, older women have a greater degree of mechanical ventilatory constraint (i.e. work of breathing and expiratory flow limitation) than their male counterparts, which may lead to a greater perceived intensity of dyspnoea. Using a single-blind randomized study design, we experimentally manipulated the magnitude of mechanical ventilatory constraint during moderate-intensity exercise at ventilatory threshold in healthy older men and women. We found that changes in the magnitude of mechanical ventilatory constraint within the physiological range had no effect on dyspnoea in healthy older adults. When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea., Abstract: We aimed to determine the effect of manipulating mechanical ventilatory constraint during submaximal exercise on dyspnoea in older men and women. Eighteen healthy subjects (aged 60-80 years; nine men and nine women) completed two days of testing. On day 1, subjects were assessed for pulmonary function and performed a maximal incremental cycle exercise test. On day 2, subjects performed three 6-min bouts of cycling at ventilatory threshold, in a single-blind randomized manner, while breathing: (i) normoxic helium-oxygen (HEL) to reduce the work of breathing (W b ) and alleviate expiratory flow limitation (EFL); (ii) through an inspiratory resistance (RES) of ∼5 cmH 2 O L -1  s -1 to increase W b ; and (iii) ambient air as a control (CON). Oesophageal pressure, diaphragm electromyography, and sensory responses (category-ratio 10 Borg scale) were monitored throughout exercise. During the HEL condition, there was a significant decrease in W b (men: -21 ± 6%, women: -17 ± 10%) relative to CON (both P < 0.01). Moreover, if EFL was present during CON (four men and five women), it was alleviated during HEL. Conversely, during the RES condition, W b (men: 42 ± 19%, women: 50 ± 16%) significantly increased relative to CON (both P < 0.01). There was no main effect of sex on W b (P = 0.59). Across conditions, women reported significantly higher dyspnoea intensity than men (2.9 ± 0.9 vs. 1.9 ± 0.8 Borg scale units, P < 0.05). Despite significant differences in the degree of mechanical ventilatory constraint between conditions, the intensity of dyspnoea was unaffected, independent of sex (P = 0.46). When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Key Points: Diaphragmatic fatigue (DF) elicits a sympathetically mediated metaboreflex resulting in increased heart rate, blood pressure and limb vascular resistance. Women may be more resistant to DF compared to men, and therefore it was hypothesised that women would experience an attenuated inspiratory muscle metaboreflex during inspiratory pressure-threshold loading (PTL) performed to task failure. At the time of PTL task failure, the severity of DF was not different between sexes; however, inspiratory muscle endurance time was significantly longer in women than in men. For a given cumulative diaphragmatic force output, the severity of DF was less in women than in men. Women exhibited a blunted cardiovascular response to inspiratory resistance (i.e. metaboreflex) that may have implications for exercise tolerance., Abstract: Diaphragmatic fatigue (DF) elicits reflexive increases in sympathetic vasomotor outflow (i.e. metaboreflex). There is some evidence suggesting women may be more resistant to DF compared to men, and therefore may experience an attenuated inspiratory muscle metaboreflex. To this end, we sought to examine the cardiovascular response to inspiratory resistance in healthy young men (n = 9, age = 24 ± 3 years) and women (n = 9, age = 24 ± 3 years). Subjects performed isocapnic inspiratory pressure-threshold loading (PTL, 60% maximal inspiratory mouth pressure) to task failure. Diaphragmatic fatigue was assessed by measuring transdiaphragmatic twitch pressure (P di,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial pressure (MAP) were measured beat-by-beat throughout PTL via photoplethysmography, and low-frequency systolic pressure (LF SBP ; a surrogate for sympathetic vasomotor tone) calculated from arterial waveforms using power spectrum analysis. At PTL task failure, the degree of DF was similar between sexes (∼23% reduction in P di,tw ; P = 0.33). However, time to task failure was significantly longer in women than in men (27 ± 11 vs. 16 ± 11 min, respectively; P = 0.02). Women exhibited less of an increase in HR (13 ± 8 vs. 19 ± 12 bpm; P = 0.02) and MAP (10 ± 8 vs. 14 ± 9 mmHg; P = 0.01), and significantly lower LF SBP (23 ± 11 vs. 34 ± 8 mmHg 2 ; P = 0.04) during PTL compared to men. An attenuation of the inspiratory muscle metaboreflex may influence limb and respiratory muscle haemodynamics with implications for exercise performance., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Key Points: High work of breathing and exercise-induced arterial hypoxaemia (EIAH) can decrease O 2 delivery and exacerbate exercise-induced quadriceps fatigue in healthy men. Women have a higher work of breathing during exercise, dedicate a greater fraction of whole-body V̇O2 towards their respiratory muscles and develop EIAH. Despite a greater reduction in men's work of breathing, the attenuation of quadriceps fatigue was similar between the sexes. The degree of EIAH was similar between sexes, and regardless of sex, those who developed the greatest hypoxaemia during exercise demonstrated the most attenuation of quadriceps fatigue. Based on our previous finding that women have a greater relative oxygen cost of breathing, women appear to be especially susceptible to work of breathing-related changes in quadriceps muscle fatigue., Abstract: Reducing the work of breathing or eliminating exercise-induced arterial hypoxaemia (EIAH) during exercise decreases the severity of quadriceps fatigue in men. Women have a greater work of breathing during exercise, dedicate a greater fraction of whole-body V̇O2 towards their respiratory muscles, and demonstrate EIAH, suggesting women may be especially susceptible to quadriceps fatigue. Healthy subjects (8 male, 8 female) completed three constant load exercise tests over 4 days. During the first (control) test, subjects exercised at ∼85% of maximum while arterial blood gases and work of breathing were assessed. Subsequent constant load exercise tests were iso-time and iso-work rate, but with EIAH prevented by inspiring hyperoxic gas or work of breathing reduced via a proportional assist ventilator (PAV). Quadriceps fatigue was assessed by measuring force in response to femoral nerve stimulation. For both sexes, quadriceps force was equally reduced after the control trial (-27 ± 2% baseline) and was attenuated with hyperoxia and PAV (-18 ± 1 and -17 ± 2% baseline, P < 0.01, respectively), with no sex difference. EIAH was similar between the sexes, and regardless of sex, subjects with the lowest oxyhaemoglobin saturation during the control test had the greatest quadriceps fatigue attenuation with hyperoxia (r 2  = 0.79, P < 0.0001). For the PAV trial, despite reducing the work of breathing to a greater degree in men (men: 60 ± 5, women: 75 ± 6% control, P < 0.05), the attenuation of quadriceps fatigue was similar between the sexes (36 ± 4 vs. 37 ± 7%). Owing to a greater relative V̇O2 of the respiratory muscles in women, less of a change in work of breathing is needed to reduce quadriceps fatigue., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

To determine the contribution of convective and diffusive limitations to V̇(O2peak) during exercise in humans, oxygen transport and haemodynamics were measured in 11 men (22 ± 2 years) during incremental (IE) and 30 s all-out cycling sprints (Wingate test, WgT), in normoxia (Nx, P(IO2): 143 mmHg) and hypoxia (Hyp, P(IO2): 73 mmHg). Carboxyhaemoglobin (COHb) was increased to 6-7% before both WgTs to left-shift the oxyhaemoglobin dissociation curve. Leg V̇(O2) was measured by the Fick method and leg blood flow (BF) with thermodilution, and muscle O2 diffusing capacity (D(MO2)) was calculated. In the WgT mean power output, leg BF, leg O2 delivery and leg V̇(O2) were 7, 5, 28 and 23% lower in Hyp than Nx (P < 0.05); however, peak WgT D(MO2) was higher in Hyp (51.5 ± 9.7) than Nx (20.5 ± 3.0 ml min(-1) mmHg(-1), P < 0.05). Despite a similar P(aO2) (33.3 ± 2.4 and 34.1 ± 3.3 mmHg), mean capillary P(O2) (16.7 ± 1.2 and 17.1 ± 1.6 mmHg), and peak perfusion during IE and WgT in Hyp, D(MO2) and leg V̇(O2) were 12 and 14% higher, respectively, during WgT than IE in Hyp (both P < 0.05). D(MO2) was insensitive to COHb (COHb: 0.7 vs. 7%, in IE Hyp and WgT Hyp). At exhaustion, the Y equilibration index was well above 1.0 in both conditions, reflecting greater convective than diffusive limitation to the O2 transfer in both Nx and Hyp. In conclusion, muscle V̇(O2) during sprint exercise is not limited by O2 delivery, O2 offloading from haemoglobin or structure-dependent diffusion constraints in the skeletal muscle. These findings reveal a remarkable functional reserve in muscle O2 diffusing capacity., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Key Points: The oxygen cost of breathing represents a significant fraction of total oxygen uptake during intense exercise. At a given ventilation, women have a greater work of breathing compared with men, and because work is linearly related to oxygen uptake we hypothesized that their oxygen cost of breathing would also be greater. For a given ventilation, women had a greater absolute oxygen cost of breathing, and this represented a greater fraction of total oxygen uptake. Regardless of sex, those who developed expiratory flow limitation had a greater oxygen cost of breathing at maximal exercise. The greater oxygen cost of breathing in women indicates that a greater fraction of total oxygen uptake (and possibly cardiac output) is directed to the respiratory muscles, which may influence blood flow distribution during exercise., Abstract: We compared the oxygen cost of breathing (V̇O2 RM ) in healthy men and women over a wide range of exercise ventilations (V̇E). Eighteen subjects (nine women) completed 4 days of testing. First, a step-wise maximal cycle exercise test was completed for the assessment of spontaneous breathing patterns. Next, subjects were familiarized with the voluntary hyperpnoea protocol used to estimate V̇O2 RM . During the final two visits, subjects mimicked multiple times (four to six) the breathing patterns associated with five or six different exercise stages. Each trial lasted 5 min, and on-line pressure-volume and flow-volume loops were superimposed on target loops obtained during exercise to replicate the work of breathing accurately. At ∼55 l min(-1) V̇E, V̇O2 RM was significantly greater in women. At maximal ventilation, the absolute V̇O2 RM was not different (P > 0.05) between the sexes, but represented a significantly greater fraction of whole-body V̇O2 in women (13.8 ± 1.5 vs. 9.4 ± 1.1% V̇O2). During heavy exercise at 92 and 100% V̇O2max, the unit cost of V̇E was +0.7 and +1.1 ml O2 l(-1) greater in women (P < 0.05). At V̇O2max, men and women who developed expiratory flow limitation had a significantly greater V̇O2 RM than those who did not (435 ± 44 vs. 331 ± 30 ml O2  min(-1) ). In conclusion, women have a greater V̇O2 RM for a given V̇E, and this represents a greater fraction of whole-body V̇O2. The greater V̇O2 RM in women may have implications for the integrated physiological response to exercise., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Key Points: Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased by acute hypoxia during rest by unknown mechanisms. Oral administration of acetazolamide blunts the pulmonary vascular pressure response to acute hypoxia, thus permitting the observation of IPAVA blood flow with minimal pulmonary pressure change. Hypoxic pulmonary vasoconstriction was attenuated in humans following acetazolamide administration and partially restored with bicarbonate infusion, indicating that the effects of acetazolamide on hypoxic pulmonary vasoconstriction may involve an interaction between arterial pH and PCO2. We observed that IPAVA blood flow during hypoxia was similar before and after acetazolamide administration, even after acid-base status correction, indicating that pulmonary pressure, pH and PCO2 are unlikely regulators of IPAVA blood flow., Abstract: 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 Pa,CO2. AZ decreased pH (-0.08 ± 0.01), [HCO3(-)] (-7.1 ± 0.7 mmol l(-1)) and Pa,CO2 (-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 Pa,CO2., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

The purpose of this study was to characterize exercise-induced arterial hypoxaemia (EIAH), pulmonary gas exchange and respiratory mechanics during exercise, in young healthy women. We defined EIAH as a >10 mmHg decrease in arterial oxygen tension ( ) during exercise compared to rest. We used a heliox inspirate to test the hypothesis that mechanical constraints contribute to EIAH. Subjects with a spectrum of aerobic capacities (n = 30; maximal oxygen consumption ( ) = 49 ± 1, range 28-62 ml kg(-1) min(-1)) completed a stepwise treadmill test and a subset (n = 18 with EIAH) completed a constant load test (~85% ) with heliox gas. Throughout exercise arterial blood gases, oxyhaemoglobin saturation ( ), the work of breathing (WOB) and expiratory flow limitation (EFL) were assessed. Twenty of the 30 women developed EIAH with a nadir and ranging from 58 to 88 mmHg and 87 to 96%, respectively. At maximal exercise, was inversely related to (r = -0.57, P < 0.05) with notable exceptions where some subjects with low aerobic fitness levels demonstrated EIAH. Subjects with EIAH had a greater (51 ± 1 vs. 43 ± 2 ml kg(-1) min(-1)), lower end-exercise (93.2 ± 0.5 vs. 96.1 ± 0.3%) and a greater maximal energetic WOB (324 ± 19 vs. 247 ± 23 J min(-1)), but had similar resting pulmonary function compared to those without EIAH. Most subjects developed EIAH at submaximal exercise intensities, with distinct patterns of hypoxaemia. In some subjects with varying aerobic fitness levels, mechanical ventilatory constraints (i.e. EFL) were the primary mechanism associated with the hypoxaemia during the maximal test. Mechanical ventilatory constraints also prevented adequate compensatory alveolar hyperventilation in most EIAH subjects. Minimizing mechanical ventilatory constraints with heliox inspiration partially reversed EIAH in subjects who developed EFL. In conclusion, healthy women of all aerobic fitness levels can develop EIAH and begin to do so at submaximal intensities. Mechanical ventilatory constraints are a primary mechanism for EIAH in some healthy women and prevent reversal of hypoxaemia in women for whom it is not the primary mechanism.

We hypothesized that inspiratory muscle training (IMT) would attenuate the sympathetically mediated heart rate (HR) and mean arterial pressure (MAP) increases normally observed during fatiguing inspiratory muscle work. An experimental group (Exp, n = 8) performed IMT 6 days per week for 5 weeks at 50% of maximal inspiratory pressure (MIP), while a control group (Sham, n = 8) performed IMT at 10% MIP. Pre- and post-training, subjects underwent a eucapnic resistive breathing task (RBT) (breathing frequency = 15 breaths min(-1), duty cycle = 0.70) while HR and MAP were continuously monitored. Following IMT, MIP increased significantly (P < 0.05) in the Exp group (-125 +/- 10 to -146 +/- 12 cmH(2)O; mean +/- s.e.m.) but not in the Sham group (-141 +/- 11 to -148 +/- 11 cmH(2)O). Prior to IMT, the RBT resulted in significant increases in HR (Sham: 59 +/- 2 to 83 +/- 4 beats min(-1); Exp: 62 +/- 3 to 83 +/- 4 beats min(-1)) and MAP (Sham: 88 +/- 2 to 106 +/- 3 mmHg; Exp: 84 +/- 1 to 99 +/- 3 mmHg) in both groups relative to rest. Following IMT, the Sham group observed similar HR and MAP responses to the RBT while the Exp group failed to increase HR and MAP to the same extent as before (HR: 59 +/- 3 to 74 +/- 2 beats min(-1); MAP: 84 +/- 1 to 89 +/- 2 mmHg). This attenuated cardiovascular response suggests a blunted sympatho-excitation to resistive inspiratory work. We attribute our findings to a reduced activity of chemosensitive afferents within the inspiratory muscles and may provide a mechanism for some of the whole-body exercise endurance improvements associated with IMT.

The purpose of this study was to compare the mechanics of breathing including the measurement of expiratory flow limitation, end-expiratory lung volume, end-inspiratory lung volume, and the work of breathing in endurance-trained men (n=8) and women (n=10) during cycle exercise. Expiratory flow limitation was assessed by applying a negative expiratory pressure at the mouth. End-expiratory lung volume and end-inspiratory lung volume were determined by having subjects perform inspiratory capacity manoeuvres. Transpulmonary pressure, taken as the difference between oesophageal and airway opening pressure, was plotted against volume and integrated to determine the work of breathing. Expiratory flow limitation occurred in nine females (90%) and three males (43%) during the final stage of exercise. Females had a higher relative end-expiratory lung volume (42+/-8 versus 35+/-5% forced vital capacity (FVC)) and end-inspiratory lung volume (88+/-5 versus 82+/-7% FVC) compared to males at maximal exercise (P<0.05). Women also had a higher work of breathing compared to men across a range of ventilations. On average, women had a work of breathing that was twice that of men at ventilations above 90 l min(-1). These data suggest that expiratory flow limitation may be more common in females and that they experience greater relative increases in end-expiratory lung volume and end-inspiratory lung volume at maximal exercise compared to males. The higher work of breathing in women is probably attributed to their smaller lung volumes and smaller diameter airways. Collectively, these findings suggest that women utilize a greater majority of their ventilatory reserve compared to men and this is associated with a higher cost of breathing.

We determined the effects of 10 daily exposures of intermittent hypoxia (IH; 1 h day(-1); oxyhaemoglobin saturation = 80%) on muscle sympathetic nerve activity (MSNA, peroneal nerve) and the hypoxic ventilatory response (HVR) before, during and after an acute 20 min isocapnic hypoxic exposure. We also assessed the potential parallel modulation of the ventilatory and sympathetic systems following IH. Healthy young men (n = 11; 25 +/- 1 years) served as subjects and pre- and post-IH measures of MSNA were obtained on six subjects. The IH intervention caused HVR to significantly increase (pre-IH = 0.30 +/- 0.03; post-IH = 0.61 +/- 0.12 l min(-1) %S(aO(2)) (-1)). During the 20 min hypoxic exposure sympathetic activity was significantly greater than baseline and remained above baseline after withdrawal of the hypoxic stimulus, even though oxyhaemoglobin saturation had normalized and ventilation and blood pressure had returned to baseline levels. When compared to the pre-IH trial, burst frequency increased (P < 0.01), total MSNA trended towards higher values (P = 0.06), and there was no effect on burst amplitude (P = 0.82) during the post-IH trial. Following IH the rise in MSNA burst frequency was strongly related to the change in HVR (r = 0.79, P < 0.05) suggesting that these sympathetic and ventilatory responses may have common central control.

We determined the ventilatory, cardiovascular and cerebral tissue oxygen response to two protocols of normobaric, isocapnic, intermittent hypoxia. Subjects (n = 18, male) were randomly assigned to short-duration intermittent hypoxia (SDIH, 12% O2 separated by 5 min of normoxia for 1 h) or long-duration intermittent hypoxia (LDIH, 30 min of 12% O2). Both groups had 10 exposures over a 12 day period. The hypoxic ventilatory response (HVR) was measured before each daily intermittent hypoxia exposure on days 1, 3, 5, 8, 10 and 12. The HVR was measured again 3 and 5 days after the end of intermittent hypoxia. During all procedures, ventilation, blood pressure, heart rate, arterial oxyhaemoglobin saturation and cerebral tissue oxygen saturation were measured. The HVR increased throughout intermittent hypoxia exposure regardless of protocol, and returned to baseline by day 17 (day 1, 0.84 +/- 0.50; day 12, 1.20 +/- 1.01; day 17, 0.95 +/- 0.58 l min(-1) %S(aO2)(-1); P < 0.01). The change in systolic blood pressure sensitivity (r = +0.68; P < 0.05) and the change in diastolic blood pressure sensitivity (r = +0.73; P < 0.05) were related to the change in HVR, while the change in heart rate sensitivity was not (r = +0.32; NS). The change in cerebral tissue oxygen saturation sensitivity to hypoxia was less on day 12, and returned to baseline by day 17 (day 1, -0.51 +/- 0.13; day 12, -0.64 +/- 0.18; day 17, -0.51 +/- 0.13; P < 0.001). Acute exposure to SDIH increased mean arterial pressure (+5 mmHg; P < 0.01), but LDIH did not (P > 0.05). SDIH and LDIH had similar effects on the ventilatory and cardiovascular response to acute progressive hypoxia and hindered cerebral oxygenation. Our findings indicate that the vascular processes required to control blood flow and oxygen supply to cerebral tissue in a healthy human are hindered following exposure to 12 days of isocapnic intermittent hypoxia.

1. We recently showed that fatigue of the inspiratory muscles via voluntary efforts caused a time-dependent increase in limb muscle sympathetic nerve activity (MSNA) (St Croix et al. 2000). We now asked whether limb muscle vasoconstriction and reduction in limb blood flow also accompany inspiratory muscle fatigue. 2. In six healthy human subjects at rest, we measured leg blood flow (.Q(L)) in the femoral artery with Doppler ultrasound techniques and calculated limb vascular resistance (LVR) while subjects performed two types of fatiguing inspiratory work to the point of task failure (3-10 min). Subjects inspired primarily with their diaphragm through a resistor, generating (i) 60 % maximal inspiratory mouth pressure (P(M)) and a prolonged duty cycle (T(I)/T(TOT) = 0.7); and (ii) 60 % maximal P(M) and a T(I)/T(TOT) of 0.4. The first type of exercise caused prolonged ischaemia of the diaphragm during each inspiration. The second type fatigued the diaphragm with briefer periods of ischaemia using a shorter duty cycle and a higher frequency of contraction. End-tidal P(CO2) was maintained by increasing the inspired CO(2) fraction (F(I,CO2)) as needed. Both trials caused a 25-40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation. 3. .Q(L) and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, .Q(L) subsequently decreased (-30 %) and LVR increased (50-60 %) relative to control in a time-dependent manner. This effect was present by 2 min in all subjects. During recovery, the observed changes dissipated quickly (< 30 s). Mean arterial pressure (MAP; +4-13 mmHg) and heart rate (+16-20 beats min(-1)) increased during fatiguing diaphragm contractions. 4. When central inspiratory motor output was increased for 2 min without diaphragm fatigue by increasing either inspiratory force output (95 % of maximal inspiratory pressure (MIP)) or inspiratory flow rate (5 x eupnoea), .Q(L), MAP and LVR were unchanged; although continuing the high force output trials for 3 min did cause a relatively small but significant increase in LVR and a reduction in .Q(L). 5. When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and .Q(L) increased significantly; these changes were attributed to the negative feedback effects on MSNA from augmented tidal volume. 6. Voluntary increases in inspiratory effort, in the absence of diaphragm fatigue, had no effect on .Q(L) and LVR, whereas the two types of diaphragm-fatiguing trials elicited decreases in .Q(L) and increases in LVR. We attribute these changes to a metaboreflex originating in the diaphragm. Diaphragm and forearm muscle fatigue showed very similar time-dependent effects on LVR and .Q(L).