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The purpose of this study was to compare sex-based differences in the mean arterial blood pressure (MAP) response to limb and inspiratory metaboreflex activation, during relative and absolute workloads. Healthy males ( n = 9) and females ( n = 8) completed pulmonary function testing, forearm volume and circumference measurements, and bouts of limb and inspiratory muscle exercise. The exercises performed included bouts of rhythmic handgrip exercise (RHG) and inspiratory pressure threshold loading (PTL) to task failure, performed in a randomized order and separated by 30 minutes of rest. Participants performed both RHG and PTL at predetermined relative (R) and absolute (A) workloads, while cardiopulmonary measurements were recorded continuously. A time-dependent rise in MAP was observed in all participants, regardless of sex, muscle, or workload ( P < 0.001). MAP was greater in males than females during all exercise bouts regardless of muscle group or workload ( P < 0.001). The change in MAP from baseline was also greater in males (R-RHG: Δ31 ± 12 mmHg; R-PTL: Δ31 ± 9; A-RHG: Δ35 ± 6; and A-PTL: Δ30 ± 7) than females (R-RHG: Δ21 ± 7 mmHg; R-PTL: Δ13 ± 7; A-RHG: Δ21 ± 7; and A-PTL: Δ14 ± 3) ( P < 0.001). Results from this study show that when the forearm and diaphragm perform the same relative or absolute work, the blood pressure response is statistically similar, and both responses are greater in males than females. The findings from the present study suggest that the sex-based difference in the response to metaboreflex activation is similar between the limb and respiratory musculature. NEW & NOTEWORTHY With rhythmic handgrip exercise and inspiratory pressure threshold loading there was a time-dependent rise in the blood pressure that was significantly lower in females than males. The blunted blood pressure response in females was present whether handgrip or inspiratory workload was relative or absolute. An attenuated cardiovascular response to high levels of limb or respiratory muscle work may have implications for whole body exercise in health and disease.

We tested the hypothesis that the incidence and magnitude of diaphragm fatigue following high-intensity exercise would be lower in females with a high aerobic capacity (Hi-Fit) compared with healthy females with an average aerobic fitness (Avg-Fit). Participants were assigned to groups based on their peak O 2 uptake (V̇o 2peak ) obtained during cycle exercise: Hi-Fit n = 9, V̇o 2peak ≥ 56.1 ± 3.4 mL·kg -1 ·min -1 versus Avg-Fit n = 9, V̇o 2peak ≤ 35.7 ± 4.9 mL·kg -1 ·min -1 . On the second day, diaphragm fatigue was assessed before and after constant load exercise test to exhaustion. Magnetic stimulation of the phrenic nerve roots was used to nonvolitionally assess diaphragm fatigue by measurement of transdiaphragmatic twitch pressure (P di,tw ). Both groups exercised at >90% of V̇o 2peak for a similar duration (Hi-Fit: 546.1 ± 177.8 vs. Avg-Fit: 559.3 ± 175.0 s, P = 0.9). Diaphragm fatigue was defined as a ≥15% reduction in P di,tw , approximately two times greater than the coefficient of variation. The mean group average reduction in P di,tw following exercise in the Hi-Fit (17.5%) and Avg-Fit groups (12.2%) was not different between groups ( P = 0.2). The Hi-Fit group performed exercise at a higher absolute work rate that elicited significantly greater ventilatory work and inspiratory muscle force output. The Hi-Fit group did not experience greater fatigue compared with the Avg-Fit group, which we attribute to a greater reliance on accessory respiratory muscle recruitment, to training-induced increases in the aerobic capacity of the diaphragm, or a combination of the two. In summary, aerobic fitness is not predictive of exercise-induced diaphragm fatigue in healthy females. NEW & NOTEWORTHY We hypothesized that females with a high aerobic capacity would be resistant to exercise-induced diaphragm fatigue relative to healthy but untrained females. We assessed the pressure generated by the diaphragm following exhaustive exercise by stimulating the phrenic nerves. The magnitude and incidence of fatigue were similar between groups. Despite having higher ventilatory demands during exercise highly trained females were resistant to greater diaphragm fatigue. Aerobic fitness is not predictive of exercise-induced diaphragm fatigue in females.

Given that there are both sex-based structural differences in the respiratory system and age-associated declines in pulmonary function, the purpose of this study was to assess the effects of age and sex on the metabolic cost of breathing (V̇o 2RM ) for exercise ventilations in healthy younger and older males and females. Forty healthy participants (10 young males 24 ± 3 yr; 10 young females 24 ± 3 yr; 10 older males 63 ± 3 yr, 10 older females 63 ± 6 yr) mimicked their exercise breathing patterns (voluntary hyperpnea) in the absence of exercise across a range of exercise intensities. At peak exercise, V̇o 2RM represented a significantly greater fraction of peak oxygen consumption (V̇o 2peak ) in young females, 12.7 ± 4.0%, compared with young males, 10.7 ± 3.0% ( P = 0.027), whereas V̇o 2RM represented 13.5 ± 2.3% of V̇o 2peak in older females and 13.2 ± 3.3% in older males. At relative ventilations, there was a main effect of age, with older males consuming a significantly greater fraction of V̇o 2RM (6.6 ± 1.9%) than the younger males (4.4 ± 1.3%; P = 0.012), and older females consuming a significantly greater fraction of V̇o 2RM (6.9 ± 2.5%) than the younger females (5.1 ± 1.4%; P = 0.004) at 65% V̇e max . Furthermore, both younger and older males had significantly better respiratory muscle efficiency than their female counterparts at peak exercise ( P = 0.011; P = 0.015). Similarly, younger participants were significantly more efficient than older participants (6.5 ± 1.5% vs. 5.5 ± 2.0%; P = 0.001). Normal age-related changes in respiratory function, in addition to sex-based differences in airway anatomy, appear to influence the ventilatory responses and the cost incurred to breathe during exercise. NEW & NOTEWORTHY Here we show that at moderate and high-intensity exercise, older individuals incur a higher cost to breathe than their younger counterparts. However, as individuals age, the sex difference in the cost of breathing narrows. Collectively, our findings suggest that the normative age-related changes in respiratory structure and function, and sex differences in airway anatomy, appear to influence the ventilatory responses to exercise and the oxygen cost to breathe.

Ground-level ozone (O 3 ) is a potent air pollutant well recognized to acutely induce adverse respiratory symptoms and impairments in pulmonary function. However, it is unclear how the hyperpnea of exercise may modulate these effects, and the subsequent consequences on exercise performance. We tested the hypothesis that pulmonary function and exercise capability would be diminished, and symptom development would be increased during peak real-world levels of O 3 exposure compared with room air. Twenty aerobically trained participants [13 M, 7 F; maximal O 2 uptake (V̇o 2max ), 64.1 ± 7.0 mL·kg -1 ·min -1 ] completed a three-visit double-blinded, randomized crossover trial. Following a screening visit, participants were exposed to 170 ppb O 3 or room air (<10 ppb O 3 ) on separate visits during exercise trials, consisting of a 25-min moderate-intensity warmup, 30-min heavy-intensity bout, and a subsequent time-to-exhaustion (TTE) performance test. No differences in O 2 uptake or ventilation were observed during submaximal exercise between conditions. During the TTE test, we observed significantly lower end-exercise O 2 uptake (-3.2 ± 4.3%, P = 0.004), minute ventilation (-3.2 ± 6.5%, P = 0.043), tidal volume (-3.6 ± 5.1%, P = 0.008), and a trend toward lower exercise duration in O 3 compared with room air (-10.8 ± 26.5%, P = 0.092). As decreases in O 2 uptake and alterations in respiratory pattern were also present at matched time segments between conditions, a limitation of oxygen transport seems likely during maximal exercise. A more comprehensive understanding of the direct mechanisms that limit oxygen transport during exercise in high-pollutant concentrations is key for mitigating performance changes. NEW & NOTEWORTHY We demonstrate that in highly trained endurance athletes, exposure to peak real-world levels of O 3 air pollution (170 ppb) significantly diminishes O 2 uptake along with corresponding changes in ventilation during maximal exercise. As no differences were observed during extended submaximal exercise, a combined effect of effective dose of pollution and exercise intensity on severity of responses seems likely.

We examined the relationship between the work of breathing (W b ) during exercise and in vivo measures of airway size in healthy females and males. We hypothesized that sex differences in airway luminal area would explain the larger resistive W b during exercise in females. Healthy participants ( n = 11 females and n = 11 males; 19-30 yr) completed a cycle exercise test to exhaustion where W b was assessed using an esophageal balloon catheter. On a separate day, each participant underwent a bronchoscopy procedure for optical coherence tomography measures of seven airways. In vivo measures of luminal area were made for the fourth to eighth airway generations. A composite index of airway size was calculated as the sum of the luminal area for each generation, and the total area was calculated based on Weibel's model. We found that index of airway size (males: 37.4 ± 6.3 mm 2 vs. females: 27.5 ± 7.4 mm 2 ) and airway area calculated based on Weibel's model (males: 2,274 ± 557 mm 2 vs. females: 1,594 ± 389 mm 2 ) were significantly larger in males (both P = 0.003). When minute ventilation was greater than ∼60 L·min -1 , the resistive W b was higher in females. At the highest equivalent flow achieved by all subjects, resistance to inspired flow was larger in females and significantly associated with two measures of airway size in all subjects: index of airway size ( r = 0.524, P = 0.012) and Weibel area ( r = 0.525, P = 0.012). Our findings suggest that innate sex differences in luminal area result in a greater resistive W b during exercise in females compared with males. NEW & NOTEWORTHY We hypothesized that the higher resistive work of breathing in females compared with males during high-intensity exercise is due to smaller airways. In vivo measures of the fourth to eighth airway generations made using optical coherence tomography show that females tend to have smaller airway luminal areas of the fourth to sixth airway generations. Sex differences in airway luminal area result in a greater resistive work of breathing during exercise in females compared with males.

This case report characterizes the physiological responses to incremental cycling and determines the effects of 12 wk of inspiratory muscle training (IMT) on respiratory muscle strength, exercise capacity, and dyspnea in a physically active 59-yr-old female, 4 years after a left-sided extrapleural pneumonectomy (EPP). On separate days, a symptom-limited incremental exercise test and a constant work rate (CWR) test at 75% of peak work rate (WR) were completed, followed by 12 wk of IMT and another CWR test. IMT consisted of two sessions of 30 repetitions twice daily for 5 days per week. Physiological and perceptual variables were measured throughout each exercise test. The participant had a total lung capacity that was 43% predicted post-EPP. A rapid and shallow breathing pattern was adopted throughout exercise, and the ratio of minute ventilation to carbon dioxide output was elevated for a given work rate. Oxygen uptake was 71% predicted and WR was 88% predicted. Following IMT, maximal inspiratory pressure improved by 36% (-27.1 cmH 2 O) and endurance time by 31 s, with no observable changes in any submaximal or peak cardiorespiratory variables during exercise. The intensity and unpleasantness of dyspnea increased by 2 and 3 Borg 0-10 units, respectively, at the highest equivalent submaximal exercise time achieved on both tests. Despite having undergone a significant reduction in lung volume post-EPP, the participant achieved a relatively normal peak incremental WR, which may reflect a high level of physical conditioning. This case report also demonstrates that IMT can effectively increase respiratory muscle strength several years following EPP. NEW & NOTEWORTHY Constraints on tidal volume expansion and the adoption of a rapid and shallow breathing pattern result in a ventilatory limitation and increased ventilatory inefficiency during exercise in a patient several years after extrapleural pneumonectomy (EPP). Inspiratory muscle training can effectively increase respiratory muscle strength after EPP.

Respiratory modulation of sympathetic vasomotor outflow to skeletal muscles (muscle sympathetic nerve activity; MSNA) occurs in resting humans. Specifically, MSNA is highest at end-expiration and lowest at end-inspiration during quiet, resting breathing. We tested the hypothesis that within-breath modulation of MSNA would be amplified during graded leg cycling. Thirteen ( n = 3 females) healthy young (age: 25.2 ± 4.7 yr) individuals completed all testing. MSNA (right median nerve) was measured at rest (baseline) and during semirecumbent cycle exercise at 40%, 60%, and 80% of maximal workload (W max ). MSNA burst frequency (BF) was 20.0 ± 4.0 bursts/min at baseline and was not different during exercise at 40%W max (21.3 ± 3.7 bursts/min; P = 0.292). Thereafter, MSNA BF increased significantly compared with baseline (60%W max : 31.6 ± 5.8 bursts/min; P < 0.001, 80%W max : 44.7 ± 5.3 bursts/min; P < 0.001). At baseline and all exercise intensities, MSNA BF was lowest at end-inspiration and greatest at mid-to-end expiration. The within-breath change in MSNA BF (ΔMSNA BF; end-expiration minus end-inspiration) gradually increased from baseline to 60%W max leg cycling, but no further increase appeared at 80%W max exercise. Our results indicate that within-breath modulation of MSNA is amplified from baseline to moderate intensity during dynamic exercise in young healthy individuals, and that no further potentiation occurs at higher exercise intensities. Our findings provide an important extension of our understanding of respiratory influences on sympathetic vasomotor control. NEW & NOTEWORTHY Within-breath modulation of sympathetic vasomotor outflow to skeletal muscle (muscle sympathetic nerve activity; MSNA) occurs in spontaneously breathing humans at rest. It is unknown if respiratory modulation persists during dynamic whole body exercise. We found that MSNA burst frequency was lowest at end-inspiration and highest at mid-to-end expiration during rest and graded leg cycling. Respiratory modulation of sympathetic vasomotor outflow remains intact and is amplified during dynamic whole body exercise.

Work of breathing ([Formula: see text]) derived from a single lung volume and pleural pressure is limited and does not fully characterize the mechanical work done by the respiratory musculature. It has long been known that abdominal activation increases with increasing exercise intensity, yet the mechanical work done by these muscles is not reflected in [Formula: see text]. Using optoelectronic plethysmography (OEP), we sought to show first that the volumes obtained from OEP (V CW ) were comparable to volumes obtained from flow integration (V t ) during cycling and running, and second, to show that partitioned volume from OEP could be utilized to quantify the mechanical work done by the rib cage ([Formula: see text] RC ) and abdomen ([Formula: see text] AB ) during exercise. We fit 11 subjects (6 males/5 females) with reflective markers and balloon catheters. Subjects completed an incremental ramp cycling test to exhaustion and a series of submaximal running trials. We found good agreement between V CW versus V t during cycling (bias = 0.002; P > 0.05) and running (bias = 0.016; P > 0.05). From rest to maximal exercise,[Formula: see text] AB increased by 84% (range: 30%-99%; [Formula: see text] AB : 1 ± 1 J/min to 61 ± 52 J/min). The relative contribution of the abdomen increased from 17 ± 9% at rest to 26 ± 16% during maximal exercise. Our study highlights and provides a quantitative measure of the role of the abdominal muscles during exercise. Incorporating the work done by the abdomen allows for a greater understanding of the mechanical tasks required by the respiratory muscles and could provide further insight into how the respiratory system functions during disease and injury. NEW & NOTEWORTHY We demonstrated that optoelectronic plethysmography (OEP) is a reliable tool to determine ventilatory volume changes during cycling and running, without restricting natural upper arm movements. Second, using OEP volumes coupled with pressure-derived measures, we calculated the work done by the rib cage and abdomen, respectively, during exercise. Collectively, our findings indicate that pulmonary mechanics can be accurately quantified using OEP, and abdominal work performed during ventilation contributes substantially to the overall work of the respiratory musculature.

Women are more resistant to diaphragmatic fatigue (DF) and experience an attenuated inspiratory muscle metaboreflex relative to men. The effects of such sex-based differences on whole body exercise tolerance are yet to be examined. It was hypothesized that DF induced prior to exercise would cause less of a reduction in subsequent exercise time in women compared to men. Healthy men ( n = 9, age = 24 ± 3 yr) and women ( n = 9, age = 24 ± 3 yr) completed a maximal incremental cycle test on day 1. On day 2, subjects performed isocapnic inspiratory pressure-threshold loading (PTL) to task failure followed by a constant load submaximal time-to-exhaustion (TTE) exercise test at 85% of the predetermined peak work rate. On day 3, subjects performed the same exercise test without prior induced DF. Days 2 and 3 were randomized and counterbalanced. Magnetic stimulation of the phrenic nerve roots was used to nonvolitionally assess DF by measurement of transdiaphragmatic twitch pressure ( P di,tw ). A similar degree of DF was produced in both sexes following PTL [ P di,tw (% change from baseline): M = -24.6 ± 7.8%, W = -23.1 ± 5.4%; P = 0.54)]. There was a significant reduction in TTE with prior induced DF compared with the control condition in both men (10.9 ± 3.5 min vs. 13.0 ± 3.2 min, P = 0.05) and women (10.1 ± 2.4 min vs. 12.2 ± 3.3 min, P = 0.03) that did not differ in magnitude between the sexes (M = -15.8 ± 19.5%, W = -14.5 ± 19.2%, P = 0.89). In conclusion, DF negatively and equally impairs exercise tolerance independent of sex. NEW & NOTEWORTHY Women are more resistant to diaphragmatic fatigue (DF) relative to men. The effect of DF on exercise tolerance is currently being debated. Our findings show that DF negatively and equally affects exercise tolerance in healthy men and women. Mechanisms beyond the inspiratory muscle metaboreflex (e.g., dyspnea, central fatigue, breathing pattern) may explain the absence of a sex-based difference.

Sympathetically induced vasoconstrictor modulation of local vasodilation occurs in contracting skeletal muscle during exercise to ensure appropriate perfusion of a large active muscle mass and to maintain also arterial blood pressure. In this synthesis, we discuss the contribution of group III-IV muscle afferents to the sympathetic modulation of blood flow distribution to locomotor and respiratory muscles during exercise. This is followed by an examination of the conditions under which diaphragm and locomotor muscle fatigue occur. Emphasis is given to those studies in humans and animal models that experimentally changed respiratory muscle work to evaluate blood flow redistribution and its effects on locomotor muscle fatigue, and conversely, those that evaluated the influence of coincident limb muscle contraction on respiratory muscle blood flow and fatigue. We propose the concept of a "two-way street of sympathetic vasoconstrictor activity" emanating from both limb and respiratory muscle metaboreceptors during exercise, which constrains blood flow and O 2 transport thereby promoting fatigue of both sets of muscles. We end with considerations of a hierarchy of blood flow distribution during exercise between respiratory versus locomotor musculatures and the clinical implications of muscle afferent feedback influences on muscle perfusion, fatigue, and exercise tolerance.

We examined the effects of age, sex, and their interaction on mechanical ventilatory constraint and dyspnea during exercise in 22 older (age = 68 ± 1 yr; n = 12 women) and 22 younger (age = 25 ± 1 y, n = 11 women) subjects. During submaximal exercise, older subjects had higher end-inspiratory (EILV) and end-expiratory (EELV) lung volumes than younger subjects (both P < 0.05). During maximal exercise, older subjects had similar EILV ( P > 0.05) but higher EELV than younger subjects ( P < 0.05). No sex differences in EILV or EELV were observed. We noted that women had a higher work of breathing (W b ) for a given minute ventilation (V̇e) ≥65 l/min than men ( P < 0.05) and older subjects had a higher W b for a given V̇e ≥60 l/min ( P < 0.05). No sex or age differences in W b were present at any submaximal relative V̇e. At absolute exercise intensities, older women experienced expiratory flow limitation (EFL) more frequently than older men ( P < 0.05), and older subjects were more likely to experience EFL than younger subjects ( P < 0.05). At relative exercise intensities, women and older individuals experienced EFL more frequently than men and younger individuals, respectively (both P < 0.05). There were significant effects of age, sex, and their interaction on dyspnea intensity during exercise at absolute, but not relative, intensities (all P < 0.05). Across subjects, dyspnea at 80 W was significantly correlated with indexes of mechanical ventilatory constraint (all P < 0.05). Collectively, our findings suggest age and sex have significant impacts on W b , operating lung volumes, EFL, and dyspnea during exercise. Moreover, it appears that mechanical ventilatory constraint may partially explain sex differences in exertional dyspnea in older individuals. NEW & NOTEWORTHY We found that age and sex have a significant effect on mechanical ventilatory constraint and the perception of dyspnea during exercise. We also observed that the perception of exertional dyspnea is associated with indexes of mechanical ventilatory constraint. Collectively, our results suggest that the combined influences of age and biological sex on mechanical ventilatory constraint during exercise contributes, in part, to the increased perception of dyspnea during exercise in older women.

There is evidence suggesting diaphragmatic fatigue (DF) occurs relatively early during high-intensity exercise; however, studies investigating the temporal characteristics of exercise-induced DF are limited by incongruent methodology. Eight healthy adult males (25 ± 5 yr) performed a maximal incremental exercise test on a cycle ergometer on day 1. A constant-load time-to-exhaustion (TTE) exercise test was conducted on day 2 at 60% delta between the calculated gas exchange threshold and peak work rate. Two additional constant-load exercise tests were performed at the same intensity on days 3 and 4 in a random order to either 50 or 75% TTE. DF was assessed on days 2, 3, and 4 by measuring transdiaphragmatic twitch pressure (P di,tw ) in response to cervical magnetic stimulation. DF was present after 75 and 100% TTE (≥20% decrease in P di,tw ). The magnitude of fatigue was 15.5 ± 5.7%, 23.6 ± 6.4%, and 35.0 ± 12.1% at 50, 75, and 100% TTE, respectively. Significant differences were found between 100 to 75 and 50% TTE (both P < 0.01), and 75 to 50% TTE ( P < 0.01). There was a significant relationship between the magnitude of fatigue and cumulative diaphragm force output ( r = 0.785; P < 0.001). Ventilation, the mechanical work of breathing (WOB), and pressure-time products were not different between trials ( P > 0.05). Our data indicate that exercise-induced DF presents a relatively late onset and is proportional to the cumulative WOB; thus the ability of the diaphragm to generate pressure progressively declines throughout exercise. NEW & NOTEWORTHY The notion that diaphragmatic fatigue (DF) occurs relatively early during exercise is equivocal. Our results indicate that DF occurs during high-intensity endurance exercise in healthy men and its magnitude is strongly related to the amount of pressure and work generated by respiratory muscles. Thus we conclude that the work of breathing is the major determinant of exercise-induced DF.

We asked if the higher work of breathing (Wb) during exercise in women compared with men is explained by biological sex. We created a statistical model that accounts for both the viscoelastic and the resistive components of the total Wb and independently compares the effects of biological sex. We applied the model to esophageal pressure-derived Wb values obtained during an incremental cycle test to exhaustion. Subjects were healthy men (n = 17) and women (n = 18) with a range of maximal aerobic capacities (V̇o2 max range: men = 40-68 and women = 39-60 ml·kg(-1)·min(-1)). We also calculated the dysanapsis ratio using measures of lung recoil and forced expiratory flow as index of airway caliber. By applying the model we found that the differences in the total Wb during exercise in women are due to a higher resistive Wb rather than viscoelastic Wb. We also found that the higher resistive Wb is independently explained by biological sex. To account for the known effect of lung volumes on the dysanapsis ratio we compared the sexes with an analysis of covariance procedures and found that when vital capacity was accounted for the adjusted mean dysanapsis ratio is statistically lower in women (0.17 vs. 0.25 arbitrary units; P < 0.05). Our collective findings suggest that innate sex-based differences may exist in human airways, which result in significant male-female differences in the Wb during exercise in healthy subjects., (Copyright © 2015 the American Physiological Society.)

In this study we tested the hypothesis that inspiring a low-density gas mixture (helium-oxygen; HeO2) would minimize mechanical ventilatory constraints and preferentially increase exercise performance in females relative to males. Trained male (n = 11, 31 yr) and female (n = 10, 26 yr) cyclists performed an incremental cycle test to exhaustion to determine maximal aerobic capacity (V̇o2max; male = 61, female = 56 ml·kg(-1)·min(-1)). A randomized, single-blinded crossover design was used for two experimental days where subjects completed a 5-km cycling time trial breathing humidified compressed room air or HeO2 (21% O2:balance He). Subjects were instrumented with an esophageal balloon for the assessment of respiratory mechanics. During the time trial, we assessed the ability of HeO2 to alleviate mechanical ventilatory constraints in three ways: 1) expiratory flow limitation, 2) utilization of ventilatory capacity, and 3) the work of breathing. We found that HeO2 significantly reduced the work of breathing, increased the size of the maximal flow-volume envelope, and reduced the fractional utilization of the maximal ventilatory capacity equally between men and women. The primary finding of this study was that inspiring HeO2 was associated with a statistically significant performance improvement of 0.7% (3.2 s) for males and 1.5% (8.1 s) for females (P < 0.05); however, there were no sex differences with respect to improvement in time trial performance (P > 0.05). Our results suggest that the extent of sex-based differences in airway anatomy, work of breathing, and expiratory flow limitation is not great enough to differentially affect whole body exercise performance., (Copyright © 2015 the American Physiological Society.)

We examined the control of breathing, cardiorespiratory effects, and the incidence of acute mountain sickness (AMS) in humans exposed to hypobaric hypoxia (HH) and normobaric hypoxia (NH), and under two control conditions [hypobaric normoxia (HN) and normobaric normoxia (NN)]. Exposures were 6 h in duration, and separated by 2 wk between hypoxic exposures and 1 wk between normoxic exposures. Before and after exposures, subjects (n = 11) underwent hyperoxic and hypoxic Duffin CO2 rebreathing tests and a hypoxic ventilatory response test (HVR). Inside the environmental chamber, minute ventilation (V(E)), tidal volume (V(T)), frequency of breathing (fB), blood oxygenation, heart rate, and blood pressure were measured at 5 and 30 min and hourly until exit. Symptoms of AMS were evaluated using the Lake Louise score (LLS). Both the hyperoxic and hypoxic CO2 thresholds were lower after HH and NH, whereas CO2 sensitivity was increased after HH and NH in the hypoxic test and after NH in the hyperoxic test. Values for HVR were similar across the four exposures. No major differences were observed for Ve or any other cardiorespiratory variables between NH and HH. The LLS was greater in AMS-susceptible than in AMS-resistant subjects; however, LLS was alike between HH and NH. In AMS-susceptible subjects, fB correlated positively and Vt negatively with the LLS. We conclude that 6 h of hypoxic exposure is sufficient to lower the peripheral and central CO2 threshold but does not induce differences in cardiorespiratory variables or AMS incidence between HH and NH.

Previous research has shown an inconsistent effect of hypoxia on dynamic cerebral autoregulation (dCA), which may be explained by concurrent CO2 control. To test the hypothesis that hypoxic dCA is mediated by CO2, we assessed dCA (transcranial Doppler) during and following acute normobaric isocapnic and poikilocapnic hypoxic exposures. On 2 separate days, the squat-stand maneuver was used to determine dCA in healthy subjects (n = 8; 3 women) in isocapnic and poikilocapnic hypoxia exposures (end-tidal oxygen pressure 50 Torr for 20 min). In isocapnic hypoxia, the amplitude of the cerebral blood flow response to increases and decreases in mean arterial blood pressure were elevated (i.e., increases in gain of +35 and +28%, respectively; P < 0.05). However, dCA gain to increases in pressure was reduced compared with baseline (-32%, P < 0.05) following the isocapnic hypoxia exposure. Similarly, intravenous bolus injections of sodium nitroprusside and phenylephrine in a separate group of subjects (n = 8; 4 women) also demonstrated a reduction in dCA gain to hypertension following isocapnic hypoxia. In contrast, dCA gain with the squat-stand maneuver did not significantly change from baseline during or following poikilocapnic hypoxia (P > 0.05). Our results demonstrate that dCA impairment in isocapnic hypoxia can be prevented with hypocapnia, and highlight the integrated nature of hypoxic cerebrovascular control, which is under strong CO2 influence.

We hypothesized that resting and exercise ventilatory chemosensitivity would be augmented in women when estrogen and progesterone levels are highest during the luteal phase of the menstrual cycle. Healthy, young females (n = 10; age = 23 ± 5 yrs) were assessed across one complete cycle: during early follicular (EF), late follicular (LF), early luteal, and mid-luteal (ML) phases. We measured urinary conjugates of estrogen and progesterone daily. To compare values of ventilatory chemosensitivity and day-to-day variability of measures between sexes, males (n = 10; age = 26 ± 7 yrs) were assessed on 5 nonconsecutive days during a 1-mo period. Resting ventilation was measured and hypoxic chemosensitivity assessed using an isocapnic hypoxic ventilatory response (iHVR) test. The hypercapnic ventilatory response was assessed using the Read rebreathing protocol and modified rebreathing tests. Participants completed submaximal cycle exercise in normoxia and hypoxia. We observed a significant effect of menstrual-cycle phase on resting minute ventilation, which was elevated in the ML phase relative to the EF and LF phases. Compared with males, resting end-tidal CO(2) was reduced in females during the EF and ML phases but not in the LF phase. We found that iHVR was unaffected by menstrual-cycle phase and was not different between males and females. The sensitivity to chemical stimuli was unaffected by menstrual-cycle phase, meaning that any hormone-mediated effect is of insufficient magnitude to exceed the inherent variation in these chemosensitivity measures. The ventilatory recruitment threshold for CO(2) was generally lower in women, which is suggestive of a hormonally related lowering of the ventilatory recruitment threshold. We detected no effect of menstrual-cycle phase on submaximal exercise ventilation and found that the ventilatory response to normoxic and hypoxic exercise was quantitatively similar between males and females. This suggests that feed-forward and feed-back influences during exercise over-ride the effects of naturally occurring changes in sex hormones.

There is evidence that female athletes may be more susceptible to exercise-induced arterial hypoxemia and expiratory flow limitation and have greater increases in operational lung volumes during exercise relative to men. These pulmonary limitations may ultimately lead to greater levels of diaphragmatic fatigue in women. Accordingly, the purpose of this study was to determine whether there are sex differences in the prevalence and severity of exercise-induced diaphragmatic fatigue in 38 healthy endurance-trained men (n = 19; maximal aerobic capacity = 64.0 +/- 1.9 ml x kg(-1) x min(-1)) and women (n = 19; maximal aerobic capacity = 57.1 +/- 1.5 ml x kg(-1) x min(-1)). Transdiaphragmatic pressure (Pdi) was calculated as the difference between gastric and esophageal pressures. Inspiratory pressure-time products of the diaphragm and esophagus were calculated as the product of breathing frequency and the Pdi and esophageal pressure time integrals, respectively. Cervical magnetic stimulation was used to measure potentiated Pdi twitches (Pdi,tw) before and 10, 30, and 60 min after a constant-load cycling test performed at 90% of peak work rate until exhaustion. Diaphragm fatigue was considered present if there was a >or=15% reduction in Pdi,tw after exercise. Diaphragm fatigue occurred in 11 of 19 men (58%) and 8 of 19 women (42%). The percent drop in Pdi,tw at 10, 30, and 60 min after exercise in men (n = 11) was 30.6 +/- 2.3, 20.7 +/- 3.2, and 13.3 +/- 4.5%, respectively, whereas results in women (n = 8) were 21.0 +/- 2.1, 11.6 +/- 2.9, and 9.7 +/- 4.2%, respectively, with sex differences occurring at 10 and 30 min (P < 0.05). Men continued to have a reduced contribution of the diaphragm to total inspiratory force output (pressure-time product of the diaphragm/pressure-time product of the esophagus) during exercise, whereas diaphragmatic contribution in women changed very little over time. The findings from this study point to a female diaphragm that is more resistant to fatigue relative to their male counterparts.

Hypoxia may sensitize the carotid chemoreceptors, resulting in a sustained elevation of muscle sympathetic nerve activity (MSNA) that outlasts the hypoxic stimulus. To test this hypothesis, we determined the effect of carotid body inhibition on the sustained elevation of MSNA following isocapnic hypoxia in humans. Seven healthy subjects (5 male, 2 female) breathed 100% O(2) (hyperoxia) for 1 min before (2 interventions) and after (2-3 interventions) 20 min of isocapnic hypoxia (80% arterial oxyhemoglobin saturation). MSNA was continuously recorded from the common peroneal nerve with microneurography. There was no effect of hyperoxia on MSNA before exposure to isocapnic hypoxia. During the isocapnic hypoxia exposure, there was an increase in minute ventilation and heart rate that subsided once hypoxia was terminated. In contrast, there was an increase in MSNA burst frequency that persisted for approximately 25 min after cessation of the stimulus. Hyperoxia resulted in a transient reduction in MSNA burst frequency of 28% (P < 0.05), 15% (P < 0.05), and 9% (P > 0.05) in the three posthypoxia interventions, respectively. Our results suggest that input from the carotid chemoreceptors is obligatory for the sustained elevation of MSNA initiated by chemoreflex stimulation. We attribute the decrease in MSNA to a transient hyperoxia-induced attenuation of carotid chemoreceptor sensitivity.

We sought to determine the relationship between lung size and airway size in men and women of varying stature. We also asked if men and women matched for lung size would still have differences in airway size and if so where along the pulmonary airway tree would these differences exist. We used computed tomography to measure airway luminal areas of the large and central airways. We determined airway luminal areas in men (n = 25) and women (n = 25) who were matched for age, body mass index, smoking history, and pulmonary function and in a separate set of men (n = 10) and women (n = 11) who were matched for lung size. Men had greater values for the larger airways and many of the central airways. When male and female subjects were pooled there were significant associations between lung size and airway size. Within the male and female groups the magnitudes of these associations were decreased or nonsignificant. In males and females matched for lung size women had significantly smaller airway luminal areas. The larger conducting airways in females are significantly smaller than those of males even after controlling for lung size.

The purpose of this study was to compare chemoresponses following two different intermittent hypoxia (IH) protocols in humans. Ten men underwent two 7-day courses of poikilocapnic IH. The long-duration IH (LDIH) protocol consisted of daily 60-min exposures to normobaric 12% O(2). The short-duration IH (SDIH) protocol comprised twelve 5-min bouts of 12% O(2), separated by 5-min bouts of room air, daily. Isocapnic hypoxic ventilatory response (HVR) was measured daily during the protocol and 1 and 7 days following. Hypercapnic ventilatory response (HCVR) and CO(2) threshold and sensitivity (by the modified Read rebreathing technique) were measured on days 1, 8, and 14. Following 7 days of IH, the mean HVR was significantly increased from 0.47 +/- 0.07 and 0.47 +/- 0.08 to 0.70 +/- 0.06 and 0.79 +/- 0.06 l.min(-1).%Sa(O(2))(-1) (LDIH and SDIH, respectively), where %Sa(O(2)) is percent arterial oxygen saturation. The increase in HVR reached a plateau after the third day. One week post-IH, HVR values were unchanged from baseline. HCVR increased from 3.0 +/- 0.4 to 4.0 +/- 0.5 l.min(-1).mmHg(-1). In both the hyperoxic and hypoxic modified Read rebreathing tests, the slope of the CO(2)/ventilation plot was unchanged by either intervention, but the CO(2)/ventilation curve shifted to the left following IH. There were no correlations between the changes in response to hypoxia and hypercapnia. There were no significant differences between the two IH protocols for any measures, indicating that comparable changes in chemoreflex control occur with either protocol. These results also suggest that the two methods of measuring CO(2) response are not completely concordant and that the changes in CO(2) control do not correlate with the increase in the HVR.

Noninvasive imaging techniques have been used to assess pulmonary edema following exercise but results remain equivocal. Most studies examining this phenomenon have used male subjects while the female response has received little attention. Some suggest that women, by virtue of their smaller lungs, airways, and diffusion surface areas may be more susceptible to pulmonary limitations during exercise. Accordingly, the purpose of this study was to determine if intense normobaric hypoxic exercise could induce pulmonary edema in women. Baseline lung density was obtained in eight highly trained female cyclists (mean +/- SD: age = 26 +/- 7 yr; height = 172.2 +/- 6.7 cm; mass = 64.1 +/- 6.7 kg; Vo(2max) = 52.2 +/- 2.2 ml.kg(-1).min(-1)) using computed tomography (CT). CT scans were obtained at the level of the aortic arch, the tracheal carina, and the superior end plate of the tenth thoracic vertebra. While breathing 15% O(2), subjects then performed five 2.5-km cycling intervals [mean power = 212 +/- 31 W; heart rate (HR) = 94.5 +/- 2.2%HRmax] separated by 5 min of recovery. Throughout the intervals, subjects desaturated to 82 +/- 4%, which was 13 +/- 2% below resting hypoxic levels. Scans were repeated 44 +/- 8 min following exercise. Mean lung density did not change from pre (0.138 +/- 0.014 g/ml)- to postexercise (0.137 +/- 0.011 g/ml). These findings suggest that pulmonary edema does not occur in highly trained females following intense normobaric hypoxic exercise.

The purpose of this study was to examine the effects of exercise on extravascular lung water as it may relate to pulmonary gas exchange. Ten male humans underwent measures of maximal oxygen uptake (Vo2 max) in two conditions: normoxia (N) and normobaric hypoxia of 15% O2 (H). Lung density was measured by quantified MRI before and 48.0 +/- 7.4 and 100.7 +/- 15.1 min following 60 min of cycling exercise in N (intensity = 61.6 +/- 9.5% Vo2 max) and 55.5 +/- 9.8 and 104.3 +/- 9.1 min following 60 min cycling exercise in H (intensity = 65.4 +/- 7.1% hypoxic Vo2 max), where Vo2 max = 65.0 +/- 7.5 ml x kg(-1) x min(-1) (N) and 54.1 +/- 7.0 ml x kg(-1) x min(-1) (H). Two subjects demonstrated mild exercise-induced arterial hypoxemia (EIAH) [minimum arterial oxygen saturation (SaO2 min) = 94.5% and 93.8%], and seven subjects demonstrated moderate EIAH (SaO2 min = 91.4 +/- 1.1%) as measured noninvasively during the Vo2 max test in N. Mean lung densities, measured once preexercise and twice postexercise, were 0.177 +/- 0.019, 0.181 +/- 0.019, and 0.173 +/- 0.019 g/ml (N) and 0.178 +/- 0.021, 0.174 +/- 0.022, and 0.176 +/- 0.019 g/ml (H), respectively. No significant differences (P > 0.05) were found in lung density following exercise in either condition or between conditions. Transient interstitial pulmonary edema did not occur following sustained steady-state cycling exercise in N or H, indicating that transient edema does not result from pulmonary capillary leakage during sustained submaximal exercise.

Ventilatory responsiveness to hypoxia (HVR) has been reported to be different between highly trained endurance athletes and healthy sedentary controls. However, a linkage between aerobic capacity and HVR has not been a universal finding. The purpose of this study was to examine the relationship between HVR and maximal oxygen consumption (VO2 max) in healthy men with a wide range of aerobic capacities. Subjects performed a HVR test followed by an incremental cycle test to exhaustion. Participants were classified according to their maximal aerobic capacity. Those with a VO2 max of >or=60 ml x kg(-1) x min(-1) were considered highly trained (n = 13); those with a VO2 max of 50-60 ml x kg(-1) x min(-1) were considered moderately-trained (n = 18); and those with a VO2 max of <50 ml x kg(-1) x min(-1) were considered untrained (n = 24). No statistical differences were detected between the three groups for HVR (P > 0.05), and the HVR values were variable within each group (range: untrained = 0.28-1.61, moderately trained = 0.23-2.39, and highly trained = 0.08-1.73 l x min.%arterial O2 saturation(-1)). The relationship between HVR and VO2 max was not statistically significant (r = -0.1723; P > 0.05). HVR was also unrelated to maximal minute ventilation and ventilatory equivalents for O2 and CO2. We found that a spectrum of hypoxic ventilatory control is present in well-trained endurance athletes and moderately and untrained men. We interpret these observations to mean that other factors are more important in determining hypoxic ventilatory control than physical conditioning per se.

Autonomic dysreflexia (AD) can occur during penile vibratory stimulation in men with spinal cord injury, but this is variable, and the association with lesion level is unclear. The purpose of this study was to characterize the cardiovascular responses to penile vibratory stimulation in men with spinal cord injury. We hypothesized that those with cervical injuries would demonstrate a greater degree of AD compared with men with thoracic injuries. We also questioned whether the rise in blood pressure could be attenuated by sildenafil citrate. Participants were classified as having cervical (n = 8) or thoracic (n = 5) injuries. While in a supine position, subjects were instrumented with an ECG, and arterial blood pressure was determined beat by beat. Subjects reported to the laboratory twice and received an oral dose of sildenafil citrate (25-100 mg) or no medication. Penile vibratory stimulation was performed using a handheld vibrator to the point of ejaculation. At ejaculation during the nonmedicated trials, the cervical group had a significant decrease in heart rate (-5-10 beats/min) and increase in mean arterial blood pressure (+70-90 mmHg) relative to resting conditions, whereas the thoracic group had significant increases in both heart rate (+8-15 beats/min) and mean arterial pressure (+25-30 mmHg). Sildenafil citrate had no effect on the change in heart rate or mean arterial pressure in either group. In summary, men with cervical injuries had more pronounced AD during penile vibratory stimulation than men with thoracic injuries. Administration of sildenafil citrate had no effect on heart rate or blood pressure during penile vibratory stimulation in men with spinal cord injury.

We hypothesized that contractions of the expiratory muscles carried out to the point of task failure would cause an increase in muscle sympathetic nerve activity (MSNA). We measured MSNA directly in six healthy men during resisted expiration (60% maximal expiratory pressure) leading to task failure with long [breathing frequency (f(b)) = 15 breaths/min; expiratory time (TE)/total respiratory cycle duration (TT) = 0.7] and short (f(b) = 30 breaths/min; TE/TT = 0.4) TE. Both of these types of expiratory muscle contractions elicited time-dependent increases in MSNA burst frequency that averaged +139 and +239%, respectively, above baseline at end exercise. The increased MSNA coincided with increases in mean arterial pressure (MAP) for both the long-TE (+28 +/- 6 mmHg) and short-TE (+22 +/- 14 mmHg) trials. Neither MSNA nor MAP changed when the breathing patterns and increased tidal volume of the task failure trials were mimicked without resistance or task failure. Furthermore, very high levels of expiratory motor output (95% maximal expiratory pressure; f(b) = 12 breaths/min; TE/TT = 0.35) and high rates of expiratory flow and expiratory muscle shortening without task failure (no resistance; f(b) = 45 breaths/min; TE/TT = 0.4; tidal volume = 1.9 x eupnea) had no effect on MSNA or MAP. Within-breath analysis of the short-expiration trials showed augmented MSNA at the onset of and throughout expiration that was consistent with an influence of high levels of central expiratory motor output. Thus high-intensity contractions of expiratory muscles to the point of task failure caused a time-dependent sympathoexcitation; these effects on MSNA were similar in their time dependency to those caused by high-intensity rhythmic contractions of the diaphragm and forearm muscles taken to the point of task failure. The evidence suggests that these effects are mediated primarily via a muscle metaboreflex with a minor, variable contribution from augmented central expiratory motor output.

This study tested the effects of inhaled nitric oxide [NO; 20 parts per million (ppm)] during normoxic and hypoxic (fraction of inspired O(2) = 14%) exercise on gas exchange in athletes with exercise-induced hypoxemia. Trained male cyclists (n = 7) performed two cycle tests to exhaustion to determine maximal O(2) consumption (VO(2 max)) and arterial oxyhemoglobin saturation (Sa(O(2)), Ohmeda Biox ear oximeter) under normoxic (VO(2 max) = 4.88 +/- 0.43 l/min and Sa(O(2)) = 90.2 +/- 0.9, means +/- SD) and hypoxic (VO(2 max) = 4.24 +/- 0.49 l/min and Sa(O(2)) = 75.5 +/- 4.5) conditions. On a third occasion, subjects performed four 5-min cycle tests, each separated by 1 h at their respective VO(2 max), under randomly assigned conditions: normoxia (N), normoxia + NO (N/NO), hypoxia (H), and hypoxia + NO (H/NO). Gas exchange, heart rate, and metabolic parameters were determined during each condition. Arterial blood was drawn at rest and at each minute of the 5-min test. Arterial PO(2) (Pa(O(2))), arterial PCO(2), and Sa(O(2)) were determined, and the alveolar-arterial difference for PO(2) (A-aDO(2)) was calculated. Measurements of Pa(O(2)) and Sa(O(2)) were significantly lower and A-aDO(2) was widened during exercise compared with rest for all conditions (P < 0.05). No significant differences were detected between N and N/NO or between H and H/NO for Pa(O(2)), Sa(O(2)) and A-aDO(2) (P > 0.05). We conclude that inhalation of 20 ppm NO during normoxic and hypoxic exercise has no effect on gas exchange in highly trained cyclists.

The effect of incremental exercise to exhaustion on the change in pulmonary clearance rate (k) of aerosolized (99m)Tc-labeled diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) and the relationship between k and arterial PO(2) (Pa(O(2))) during heavy work were investigated. Ten male cyclists (age = 25 +/- 2 yr, height = 180.9 +/- 4.0 cm, mass = 80.1 +/- 9.5 kg, maximal O(2) uptake = 5. 25 +/- 0.35 l/min, mean +/- SD) completed a pulmonary clearance test shortly (39 +/- 8 min) after a maximal O(2) uptake test. Resting pulmonary clearance was completed >/=24 h before or after the exercise test. Arterial blood was sampled at rest and at 1-min intervals during exercise. Minimum Pa(O(2)) values and maximum alveolar-arterial PO(2) difference ranged from 73 to 92 Torr and from 30 to 55 Torr, respectively. No significant difference between resting k and postexercise k for the total lung (0.55 +/- 0.20 vs. 0. 57 +/- 0.17 %/min, P > 0.05) was observed. Pearson product-moment correlation indicated no significant linear relationship between change in k for the total lung and minimum Pa(O(2)) (r = -0.26, P > 0.05). These results indicate that, averaged over subjects, pulmonary clearance of (99m)Tc-DTPA after incremental maximal exercise to exhaustion in highly trained male cyclists is unchanged, although the sampling time may have eliminated a transient effect. Lack of a linear relationship between k and minimum Pa(O(2)) during exercise suggests that exercise-induced hypoxemia occurs despite maintenance of alveolar epithelial integrity.