A. William Sheel

Fatiguing inspiratory muscle work causes reflex reduction in resting leg blood flow in humans

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 (Q̇L) 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 (PM) and a prolonged duty cycle (TI/TTOT= 0.7); and (ii) 60 % maximal PM and a TI/TTOT 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 PCO2 was maintained by increasing the inspired CO2 fraction (FI,CO2) as needed. Both trials caused a 25–40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation. 3 Q̇ L and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, Q̇L 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 × eupnoea), Q̇L, 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 nQ̇L. 5 When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and Q̇L 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 Q̇L and LVR, whereas the two types of diaphragm‐fatiguing trials elicited decreases in Q̇L 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 Q̇L.

Regulation of Cerebral Blood Flow During Exercise

Constant cerebral blood flow (CBF) is vital to human survival. Originally thought to receive steady blood flow, the brain has shown to experience increases in blood flow during exercise. Although increases have not consistently been documented, the overwhelming evidence supporting an increase may be a result of an increase in brain metabolism. While an increase in metabolism may be the underlying causative factor for the increase in CBF during exercise, there are many modulating variables. Arterial blood gas tensions, most specifically the partial pressure of carbon dioxide, strongly regulate CBF by affecting cerebral vessel diameter through changes in pH, while carbon dioxide reactivity increases from rest to exercise. Muscle mechanoreceptors may contribute to the initial increase in CBF at the onset of exercise, after which exercise-induced hyperventilation tends to decrease flow by pial vessel vasoconstriction. Although elite athletes may benefit from hyperoxia during intense exercise, cerebral tissue is well protected during exercise, and cerebral oxygenation does not appear to pose a limiting factor to exercise performance. The role of arterial blood pressure is important to the increase in CBF during exercise; however, during times of acute hypotension such as during diastole at high-intensity exercise or post-exercise hypotension, cerebral autoregulation may be impaired. The impairment of an increase in cardiac output during exercise with a large muscle mass similarly impairs the increase in CBF velocity, suggesting that cardiac output may play a key role in the CBF response to exercise. Glucose uptake and CBF do not appear to be related; however, there is growing evidence to suggest that lactate is used as a substrate when glucose levels are low. Traditionally thought to have no influence, neural innervation appears to be a protective mechanism to large increases in cardiac output. Changes in middle cerebral arterial velocity are independent of changes in muscle sympathetic nerve activity, suggesting that sympathetic activity does not alter medium-sized arteries (middle cerebral artery).CBF does not remain steady, as seen by apparent increases during exercise, which is accomplished by a multi-factorial system, operating in a way that does not pose any clear danger to cerebral tissue during exercise under normal circumstances.

Respiratory mechanics during exercise in endurance-trained men and women.

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.

Inspiratory muscle training attenuates the human respiratory muscle metaboreflex.

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 cmH2O; mean ±s.e.m.) but not in the Sham group (−141 ± 11 to −148 ± 11 cmH2O). 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.

Respiratory influences on sympathetic vasomotor outflow in humans

We have attempted to synthesize findings dealing with four types of respiratory system influences on sympathetic outflow in the human. First, a powerful lung volume-dependent modulation of muscle sympathetic nerve activity (MSNA) occurs within each respiratory cycle showing late-inspiratory inhibition and late-expiratory excitation. Secondly, in the intact human, neither reductions in spontaneous respiratory motor output nor voluntary near-maximum increases in central respiratory motor output and inspiratory effort, per sec, influence MSNA modulation within a breath, MSNA total activity or limb vascular conductance. Thirdly, carotid chemoreceptor stimuli markedly increase total MSNA; but most of the MSNA response to chemoreceptor activation appears to be mediated independently of increased central respiratory motor output. Fourthly, repeated fatiguing contractions of the diaphragm or expiratory muscles in the human show a metaboreflex mediated time-dependent increase in MSNA and reduced vascular conductance and blood flow in the resting limb. Recent evidence suggests that these respiratory influences contribute significantly to sympathetic vasomotor outflow and to the distribution of systemic vascular conductances and blood flow in the exercising human.

Respiratory muscle training in healthy individuals: physiological rationale and implications for exercise performance.

AbstractThe respiratory system has traditionally been viewed to be capable of meeting the substantial demands for ventilation and gas exchange and the cardiopulmonary interactions imposed by short-term maximum exercise or long-term endurance exercise. Recent studies suggest that specific respiratory muscle (RM) training can improve the endurance and strength of the respiratory muscles in healthy humans. The effects of RM training on exercise performance remains controversial. When whole-body exercise performance is evaluated using submaximal fixed work-rate tests, significant improvements are seen and smaller, but significant improvements have also been reported in placebo-trained individuals. When performance is measured using time-trial type performance measures versus fixed workload tests, performance is increased to a much lesser extent with RM training. It appears that RM training influences relevant measures of physical performance to a limited extent at most. Interpretation of the collective literature is difficult because most studies have utilised relatively small sample sizes and very few studies have used appropriate control or placebo groups. Mechanisms to explain the purported improvements in exercise performance remain largely unknown. However, possible candidates include improved ratings of breathing perception, delay of respiratory muscle fatigue, ventilatory efficiency, or blood flow competition between respiratory and locomotor muscles. This review summarises the current literature on the physiology of RM training in healthy ically evaluates the possible implications for exercise performance.

Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia

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%SaO2−1; 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.

Long‐term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans

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.

Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers

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.

Sex differences in the resistive and elastic work of breathing during exercise in endurance-trained athletes

It is not known whether the high total work of breathing (WOB) in exercising women is higher due to differences in the resistive or elastic WOB. Accordingly, the purpose of this study was to determine which factors contribute to the higher total WOB during exercise in women. We performed a comprehensive analysis of previous data from 16 endurance-trained subjects (8 men and 8 women) that underwent a progressive cycle exercise test to exhaustion. Esophageal pressure, lung volumes, and ventilatory parameters were continuously monitored throughout exercise. Modified Campbell diagrams were used to partition the esophageal-pressure volume data into inspiratory and expiratory resistive and elastic components at 50, 75, 100 l/min and maximal ventilations and also at three standardized submaximal work rates (3.0, 3.5, and 4.0 W/kg). The total WOB was also compared between sexes at relative submaximal ventilations (25, 50, and 75% of maximal ventilation). The inspiratory resistive WOB at 50, 75, and 100 l/min was 67, 89, and 109% higher in women, respectively (P < 0.05). The expiratory resistive WOB was 131% higher in women at 75 l/min (P < 0.05) with no differences at 50 or 100 l/min. There were no significant sex differences in the inspiratory or expiratory elastic WOB across any absolute minute ventilation. However, the total WOB was 120, 60, 50, and 45% higher in men at 25, 50, 75, and 100% of maximal exercise ventilation, respectively (P < 0.05). This was due in large part to their much higher tidal volumes and thus higher inspiratory elastic WOB. When standardized for a given work rate to body mass ratio, the total WOB was significantly higher in women at 3.5 W/kg (239 +/- 31 vs. 173 +/- 12 J/min, P < 0.05) and 4 W/kg (387 +/- 53 vs. 243 +/- 36 J/min, P < 0.05), and this was due exclusively to a significantly higher inspiratory and expiratory resistive WOB rather than differences in the elastic WOB. The higher total WOB in women at absolute ventilations and for a given work rate to body mass ratio is due to a substantially higher resistive WOB, and this is likely due to smaller female airways relative to males and a breathing pattern that favors a higher breathing frequency.