Paolo B. Dominelli

β-adrenergic blockade reduced heart rate without affecting blood pressure in either sex. Exercise hyperemia did not differ between sexes and was unchanged with β-adrenergic blockade, even after normalizing for interindividual variability in resting blood flow and participant strength. Brachial artery dilation relative to baseline was blunted in females with propranolol, suggesting a sex-specific β-adrenergic mechanism mediating vascular control, whereas overall hyperemia was not impacted.

Dyspnoea is a multidimensional sensation of breathing discomfort that varies in sensory and affective experience. During exercise, healthy adults commonly report dyspnoea sensations of ‘air hunger’ and ‘work/effort’, with females more frequently reporting air hunger at maximal exertion. Interpreting these sex differences and their underlying mechanisms is challenging due to the complex physiological responses associated with exercise. Therefore, this study used laboratory models to target respiratory stimuli and evaluate sex‐differences in perceptual and physiological responses to dyspnoea. In a randomized crossover design, 34 healthy participants ( n = 17M; n = 17F) completed two breathing challenges. Work/effort was targeted using incremental inspiratory pressure threshold loading (IPTL). Air hunger was targeted by constraining ventilation while incrementally increasing the partial pressure of end‐tidal carbon dioxide (). Ratings of dyspnea intensity, unpleasantness, work/effort and air hunger were assessed at the end of each increment. Electromyography of the crural diaphragm (EMG _di ), sternocleidomastoid (EMG _scm ) and scalene (EMG _sca ) were measured throughout each trial. Mixed‐effects models tested sex‐by‐stimulus interactions. During IPTL, males exhibited a significantly steeper increase in dyspnoea intensity and work/effort ratings than females. These perceptual differences occurred without a concomitant sex difference in EMG _di, while EMG _scm and EMG _sca were lower in males compared to females. During hypercapnia, there were no sex‐by‐stimulus interactions for perceptual or physiological outcomes, despite significantly greater EMG _scm in females than males. These findings highlight that sex differences in dyspnoea are stimulus‐dependent, occurring during mechanical loading but not chemostimulation, and may partly reflect differences in perceptual anchoring to experience and expectation.

Peripheral hypercapnic chemosensitivity (PHC) is the ventilatory response to a brief rise in arterial carbon dioxide tension. PHC is known to increase at the onset of exercise, with no further increases with progressive exercise intensity. The mechanisms for this augmentation remain unclear but may involve central command. We examined whether PHC scales with active muscle mass by comparing small‐muscle (rhythmic handgrip, RHG), intermediate‐muscle (single‐leg extension, SLE), and large/whole‐body (cycling, BIKE) exercise. Twenty‐two healthy adults ( n = 11 females) performed RHG, SLE, and BIKE exercise. PHC was measured before and during exercise using four trials, each consisting of two inhalations of 10% carbon dioxide. All exercise modalities produced a significant increase in PHC from rest. During exercise, SLE and BIKE (0.895 ± 0.388 and 1.028 ± 0.460 L·min ⁻¹ ·mmHg ⁻¹ , respectively) elicited significantly greater PHC than RHG (0.683 ± 0.247 L·min ⁻¹ ·mmHg ⁻¹ ) ( p = 0.037 and 0.015, respectively), while SLE and BIKE were not different ( p = 0.263). Exercise sensitizes PHC regardless of recruited muscle mass, but augmentation does not scale linearly with muscle mass. As PHC increased with recruitment up to SLE, with no further increase during BIKE. These findings suggest that the augmentation of PHC is more closely associated with the transition to exercise, although the present exploratory study cannot determine the mechanism(s) responsible.

Intrathoracic pressure (ITP) modulates venous return, ventricular filling and ejection throughout the respiratory cycle, and its fluctuations are accentuated during exercise. We sought to determine whether ITP manipulation during submaximal exercise alters cardiac volumes differently in males and females. Young, healthy participants completed two protocols (both n = 30, 15 females): (i) inspiratory loaded breathing (75 W and 30% W _max ) and (ii) expiratory loaded breathing (100 W and 60% W _max ). We aimed to increase the inspiratory and expiratory load by +20 cmH ₂ O oesophageal pressure (absolute submaximal trials; 75 and 100 W) and +50% oesophageal pressure swings (relative submaximal trials; 30% and 60% W _max ). Intrathoracic pressure was measured with a balloon catheter placed in the oesophagus, and left ventricular volumes and cardiac output were determined via echocardiography. Inspiratory loading increased oesophageal pressure swings relative to spontaneous breathing at both intensities [75 W: +24.2 ± 10.2 cmH ₂ O (ITP = +77.3%); 30% W _max : +14.3 ± 8.6 cmH ₂ O (ITP = +53.1%); P < 0.0001] with no difference in stroke volume (SV) [75 W: +3.2 ± 10.1 mL (SV = +3.8%); 30% W _max : +0.7 ± 9.7 mL (SV = +0.8%); P ≥ 0.100] in either sex. Expiratory loading increased oesophageal pressure swings relative to spontaneous breathing [100 W: +23.1 ± 4.1 cmH ₂ O (ITP = +66.3%); 60% W _max : +17.1 ± 8.5 cmH ₂ O (ITP = +50.1%); P < 0.0001]. With expiratory loading, SV decreased compared to spontaneous breathing [100 W: −11.4 ± 9.7 mL (SV = −13.8%); 60% W _max : −8.3 ± 9.5 mL (SV = −10.2%); P < 0.0001] with left ventricular end‐systolic volume (LVESV) decreasing in females [100 W: −6.5 ± 4.7 mL (LVESV = −13.9%); 60% W _max : −6.1 ± 6.5 mL (LVESV = −13.1%); both P < 0.0006], but not in males [100 W: −1.9 ± 7.2 mL (LVESV = −2.6%); 60% W _max : −0.1 ± 4.8 mL (LVESV = −0.2%); P ≥ 0.409]. Overall, exercise appears to blunt any potential cardiac volume changes with inspiratory loaded breathing, whereas expiratory loaded breathing (less negative ITP) imposes a preload limitation that the exercising heart cannot compensate, thereby unmasking a female‐specific reduction in LVESV. image Key points: At rest, more negative intrathoracic pressure (ITP) with inspiratory loading lowers left ventricular end‐diastolic volume (LVEDV) and stroke volume (SV). Previous work conducted at maximal exercise shows no cardiac volume changes with inspiratory loading. The mechanisms and any sex‐based differences are unknown. During rest and exercise, less negative ITP with expiratory loading reduces LVEDV, SV and cardiac output; however, sex‐specific responses remain unclear. Inspiratory loading at submaximal exercise results in no cardiac volume changes and responses were not different between males and females. Expiratory loading at submaximal exercise reduces LVEDV, SV and cardiac output in both sexes; however, females experience greater reductions in cardiac volumes and exhibit a decline in left ventricular end‐systolic volume (LVESV). During exercise, potential cardiac volume changes associated with more negative ITP (inspiratory loading) appear to be masked by the cardiovascular responses to exercise, whereas less negative ITP (expiratory loading) imposes an uncompensated preload limitation although females attempt to counter this through LVESV reductions.

Maintaining end-tidal carbon dioxide ([ ]) at isocapnic levels during supra-respiratory compensation point (RCP) exercise significantly increased the peripheral hypercapnic chemoresponse (PHC) compared with poikilocapnic conditions. However, neither the isocapnic nor poikilocapnic exercise above RCP resulted in a significant increase in PHC compared with lower intensity exercise. Thus, although prestimulus [ ] impacts the PHC, supra-RCP exercise does not further augment the PHC beyond low intensity exercise.

Imposing moderate-intensity exercise on acute, sustained isocapnic hypoxia in close temporal proximity showed evidence of hypoxic ventilatory decline in the first 15 min of exercise. The percent decline in ventilation during exercise was smaller than the hypoxic ventilatory decline at rest, indicating a blunting of the ventilatory decline when occurring together with exercise. Duration of pre-exercise hypoxic exposure should be considered when interpreting hypoxic exercise ventilation.

Interstitial lung disease (ILD) encompasses pulmonary disorders characterized by chronic inflammation and fibrosis that disrupt pulmonary gas exchange. While ILD‐related changes in the lung parenchyma are well‐documented, less is known about how ILD affects luminal area within the large conducting airways. This retrospective, case–control study tested the hypothesis that patients with ILD would have greater large conducting airway luminal areas than healthy matched controls. Three‐dimensional reconstructions of computed tomography images were used to quantify airway luminal areas in patients with ILD (n = 82; 54% female) and healthy controls matched for age, sex, and height. Patients with ILD had 16%–22% greater airway luminal areas across all seven measured large conducting airways compared to controls (all p < 0.001). Among patients with ILD, males had 17%–34% greater height‐normalized airway luminal areas than females (all p < 0.05). These data provide evidence that ILD is associated with greater large conducting airway luminal area, even when matched for key demographic factors. Consistent with observations in health, males with ILD exhibited greater height‐normalized airway size than females. These findings offer new insight into airway remodeling in ILD and highlight potential sex differences in airway luminal area.

During inspiratory pressure‐threshold loading (ITL), the inspiratory muscle metaboreflex (IMM) increases respiratory muscle blood flow, but its effect on diaphragm blood flow (Q̇_di) and fatigue in humans, is unclear. Females exhibit an attenuated IMM compared to males during diaphragmatic loading, suggesting less diaphragm blood flow impedance and metaboreflex activation. We hypothesized that diaphragm hyperaemia would relate positively to metaboreflex sensitivity (i.e. mean arterial pressure change; ΔMAP) and fatigue development (i.e. transdiaphragmatic twitch pressure change; ΔP_di,tw), and be less for females than males. Healthy males and females (11 males and 11 females) completed 6 min of ITL targeting a transdiaphragmatic pressure (P_di) of 80 cmH₂O. Contrast‐enhanced ultrasound was used to quantify Q̇_di at baseline, 50% and 100% of task completion. The ΔMAP during loading and the pre‐ to post‐task ΔP_di,tw, via bilateral phrenic nerve electrical stimulation, assessed metaboreflex activation and fatigue, respectively. The accumulated pressure‐time‐product for P_di (14,177±1,497 cmH₂O·s; mean ± SD) and percentage of maximal P_di (%P_di,max, 51 ± 8%) was not different between sexes (P > 0.600). At 100% of task completion, IMM activation (ΔMAP, +21 mmHg; 95% confidence interval (CI) = 18–24 mmHg; P < 0.0001), diaphragm fatigue (ΔP_di,tw, −18.1 mmHg; 95% CI = −22.2 to −13.9%; P < 0.0001) and hyperaemia (ΔQ̇_di, +15.8 AU s⁻¹; 95% CI = 12.5–19.1 AU s⁻¹; P < 0.0001) did not differ between sexes (P ≥ 0.352). There was a significant positive relationship between ΔQ̇_di and %P_di,max (r^2 = 0.211; P = 0.0317), but no relationship between ΔQ̇_di and either ΔMAP (r^2 = 0.011; P = 0.638) or ΔP_di,tw (r^2 = 0.001, P = 0.914). Our data demonstrate that diaphragm hyperaemia relates to relative exercise intensity (%P_di,max) but is not associated with metaboreflex sensitivity, diaphragm fatigue or sex. image Key points: The inspiratory muscle metaboreflex is activated during fatiguing diaphragmatic loading to redistribute blood flow to working muscles. How diaphragm hyperaemia relates to metaboreflex sensitivity or diaphragm fatigue development is unknown. Compared to males, females are reported to have an attenuated inspiratory muscle metaboreflex during both equal absolute and relative intensities, as well as greater diaphragm fatigue resistance during absolute workloads. We investigated whether these sex‐based differences result from a lesser hyperaemic response for females compared to males. We found that hyperaemia of the diaphragm was positively correlated with fractional transdiaphragmatic pressure but did not relate to the degree of diaphragm fatigue or metaboreflex sensitivity. Females and males without differences in diaphragmatic strength did not differ in the magnitude of diaphragm hyperaemia, metaboreflex response, or fatigue development.

The magnitude of exercise-induced bronchodilation (EIBD) was not different in healthy young males and females. Both sexes exhibited a ∼5% improvement in forced expired volume in 1 s and an 8%–20% improvement in mid-expiratory flows. When accounting for thoracic gas compression using a volume displacement plethysmograph, the lack of sex differences in EIBD persisted but the absolute magnitude of EIBD was diminished.

Temporary residence at 3,500 m resulted in a greater resting peripheral hypercapnic chemosensitivity than at 1,100 m. Exercise increases hypercapnic sensitivity of the peripheral chemoreceptors from rest at both 1,100 m and 3,500 m, but the magnitude of increase from rest was not different between altitudes. The mechanism for the increased peripheral hypercapnic chemosensitivity induced by exercise is likely unaffected by altitude exposure.