Dose-dependent inhibition of cold air-induced bronchoconstriction by atropine

We undertook a study to demonstrate whether inhalation of atropine could inhibit cold air-induced bronchoconstriction in a dose-dependent fashion. In seven subjects with asthma we assessed the effects of placebo and of various doses of inhaled atropine (0.13-2.08 mg) on a base-line specific airway resistance (sRaw) and on the increase in sRaw produced by 5 min of voluntary eucapnic hyperventilation with subfreezing air at -17 degrees C. We also assessed the effect of the lowest doses of atropine on the increase in sRaw produced by five breaths of 1.0% metacholine. Atropine in doses of 0.13 or 0.26 mg caused a maximal reduction in base-line sRaw and completely inhibited the effect of 1.0% methacholine on sRaw, but it did not inhibit the bronchomotor response to cold air. Higher doses of atropine did inhibit the effect of cold air on sRaw in a dose-dependent fashion. The dose of atropine required to inhibit this effect of cold air varied with the increase in sRaw produced by cold air after placebo. These results suggest that cold air causes bronchoconstriction through vagal pathways and that higher doses of antimuscarinic agents are required to inhibit vagally mediated bronchoconstriction than those required to reduce base-line airway tone or to inhibit the effects of a large dose of an inhaled muscarinic agonist.     

Pulmonary response to threshold levels of sulfur dioxide (1.0 ppm) and ozone (0.3 ppm)

We exposed 22 healthy adult nonsmoking male subjects for 2 h to filtered air, 1.0 ppm sulfur dioxide (SO2), 0.3 ppm ozone (O3), or the combination of 1.0 ppm SO2 + 0.3 ppm O3. We hypothesized that exposure to near-threshold concentrations of these pollutants would allow us to observe any interaction between the two pollutants that might have been masked by the more obvious response to the higher concentrations of O3 used in previous studies. Each subject alternated 30-min treadmill exercise with 10-min rest periods for the 2 h. The average exercise ventilation measured during the last 5 min of exercise was 38 1/min (BTPS). Forced expiratory maneuvers were performed before exposure and 5 min after each of the three exercise periods. Maximum voluntary ventilation, He dilution functional residual capacity, thoracic gas volume, and airway resistance were measured before and after the exposure. After O3 exposure alone, forced expiratory measurements (FVC, FEV1.0, and FEF25-75%) were significantly decreased. The combined exposure to SO2 + O3 produced similar but smaller decreases in these measures. There were small but significant differences between the O3 and the O3 + SO2 exposure for FVC, FEV1.0, FEV2.0, FEV3.0, and FEF25-75% at the end of the 2-h exposure. We conclude that, with these pollutant concentrations, there is no additive or synergistic effect of the two pollutants on pulmonary function.     

Unrestrained acoustic plethysmograph for measuring specific airway resistance in mice.

An acoustic whole body plethysmograph was developed to estimate specific airway resistance (sRaw) in unrestrained mice. The plethysmograph uses acoustic principles to measure the thoracic breathing pattern and simultaneously measures the airflow entering and/or leaving the plethysmograph. Similarly to traditional methods utilizing a double-chamber plethysmograph, these measurements were combined to estimate sRaw. To evaluate the new system, we placed six conscious A/J mice individually in a whole body plethysmograph (Buxco System) for a 2-min exposure to aerosolized methacholine chloride dissolved in saline (0, 5, 10, and 20 mg/ml), which is known to increase sRaw in mice. Three minutes after exposure, the mice were transferred to the acoustic plethysmograph for 2 min for data collection. The mean baseline value of sRaw was 0.93+/-0.10 cmH2O.s. A dose-dependent increase in sRaw was shown, with an approximate tripling of sRaw at the highest dose. These results demonstrate the ability of the system to estimate sRaw based on plethysmograph airflow and acoustic amplitude.     

Physiological effects of hydrogen sulfide inhalation during exercise in healthy men.

Occupational exposure to hydrogen sulfide (H2S) is prevalent in a variety of industries. H2S when inhaled 1) is oxidized into a sulfate or a thiosulfate by oxygen bound to hemoglobin and 2) suppresses aerobic metabolism by inhibiting cytochrome oxidase (c and aa3) activity in the electron transport chain. The purpose of this study was to examine the acute effects of oral inhalation of H2S on the physiological responses during graded cycle exercise performed to exhaustion in healthy male subjects. Sixteen volunteers were randomly exposed to 0 (control), 0.5, 2.0, and 5.0 ppm H2S on four separate occasions. Compared with the control values, the results indicated that the heart rate and expired ventilation were unaffected as a result of the H2S exposures during submaximal and maximal exercise. The oxygen uptake had a tendency to increase, whereas carbon dioxide output had a tendency to decrease as a result of the H2S exposures, but only the 5.0 ppm exposure resulted in a significantly higher maximum oxygen uptake. Blood lactate concentrations increased significantly during submaximal and maximal exercise as a result of the 5.0 ppm exposure. Despite these large increases in lactate concentration, the maximal power output of the subjects was not significantly altered as a result of the 5.0 ppm H2S exposure. It was concluded that healthy young male subjects could safely exercise at their maximum metabolic rates while breathing 5.0 ppm H2S without experiencing a significant reduction in their maximum physical work capacity during short-term incremental exercise.     

Effect of normobaric hyperoxia on airways of normal subjects

Airway responsiveness to inhaled cholinergic agonist during the early stage of pulmonary O2 toxicity was examined to determine whether normobaric hyperoxia alters airway function. Eight healthy nonsmoking males with moderate base-line methacholine responsiveness breathed normobaric O2 (greater than or equal to 95%) over 12 h and on another occasion breathed air in an identical protocol. Vital capacity, expiratory flow, airway responsiveness to methacholine, and respiratory symptoms were measured at 0, 4, 8, and 12 h while subjects breathed O2 and 12 h afterwards. After 12 h, forced vital capacity was significantly decreased with O2 breathing but not with air breathing. At 4, 8, or 12 h of exposure and 12 h after exposure, there was no difference in methacholine sensitivity or reactivity between O2 and air-exposure trials. The earliest manifestations of pulmonary normobaric O2 toxicity in normal adults include diminished vital capacity and the onset of respiratory symptoms, but early O2 toxicity does not produce altered responsiveness to inhaled methacholine.     

Effect of SO2 on control of breathing in anesthetized cats

In seven anesthetized tracheotomized cats we studied the acute respiratory effects of SO2 inhalation at different steady-state levels of arterial CO2 tension (Paco2). During room air breathing, SO2 (0.05%) addition caused a progressive reduction in tidal volume (VT) and increases in both respiratory frequency (f) and pulmonary resistance (RL). Atropine sulfate abolished the bronchoconstriction response to SO2 and thus permitted the study of the influence of SO2 on VT and f in the absence of constricted airways. Despite marked reductions in the VT VS. PaCO2 relationships with SO2 exposure after atropine, the relationship between pulmonary ventilation (VE) and PaCO2 was not signifcantly altered. This was the case since SO2 caused solely a reduction in inspiratory duration (Ti), affecting neither the mean rate of rise of inspiratory activity (i.e., VT/Ti) nor the relationship between Ti and breath duration. Thus, airways irritation with SO2 produced rapid, shallow breathing characterized by a shortening of inspiratory and total respiratory cycle times with no change in the rate of development of inspiratory activity. The findings suggest an influence exclusively concerned with the timing of inspiration. Perhaps premature onset of inspiratory activity accounts for the observed effects.     

Ventilatory muscle recruitment in exercise with O2 in obstructed patients with mild hypoxemia

Respiratory muscle dysfunction limits exercise endurance in severe chronic airflow obstruction (CAO). To investigate whether inspiring O2 alters ventilatory muscle recruitment and improves exercise endurance, we recorded pleural (Ppl) and gastric (Pga) pressures while breathing air or 30% O2 during leg cycling in six patients with severe CAO, mild hypoxemia, and minimal arterial O2 desaturation with exercise. At rest, mean (+/- SD) transdiaphragmatic pressure (Pdi) was lower inspiring 30% O2 compared with air (23 +/- 4 vs. 26 +/- 7 cmH2O, P less than 0.05), but the pattern of Ppl and Pga contraction was identical while breathing either gas mixture. Maximal transdiaphragmatic pressure was similar breathing air or 30% O2 (84 +/- 30 vs. 77 +/- 30 cmH2O). During exercise, Pdi increased similarly while breathing air or 30% O2, but the latter was associated with a significant increase in peak inspiratory Pga and decreases in peak inspiratory Ppl and expiratory Pga. In five out of six patients, exercise endurance increased with O2 (671 +/- 365 vs. 362 +/- 227 s, P less than 0.05). We conclude that exercise with O2 alters ventilatory muscle recruitment and increases exercise endurance. During exercise inspiring O2, the diaphragm performs more ventilatory work which may prevent overloading the accessory muscles of respiration.     

Effect of 0.25 ppm ozone exposure on pulmonary damage induced by bleomycin

To study the effect of ozone in a chronically damaged lung, we used a bleomycin (BLM) induced pulmonary fibrosis model. Both endotracheal instillation of BLM and O3 exposure both produce lung inflammation and fibrosis. Oxidative stress would be a common mechanism of damage for both BLM and O3. Our aim was to assess lung injury induced by 5 and 60 days of intermittent exposure to 0.25 ppm O3 in rats with bleomycin-induced pulmonary fibrosis. Thirty-day-old Sprague Dawley rats were endotracheally instilled with BLM (1 U/100 g body weight) and, 30 days later, exposed to 0.25 ppm 03 (0.25 ppm 4 h per day, 5 days a week). Histopatology controls were instilled with saline and breathing room air. Histopathological evaluation of lungs was done 5 and 60 days after O3 exposure. BLM-induced lung damage did not change after 60 days of intermittent O3 exposure. Five days of O3 exposure increased the mean score of BLM-induced pulmonary inflammation and fibrosis (p=0.06). Frequency of bronchopneumonia increased from 1/7 to 6/6 (p <0.001), suggesting that a short-term exposure to O3 in a previously damaged lung might be a risk factor for developing further lung injury.     

Effect of route of atropine delivery on bronchospasm from cold air and methacholine

We undertook a study to determine whether the apparent disparity between the dose of inhaled atropine required to inhibit the bronchoconstriction induced by inhaled methacholine and the dose required to inhibit the bronchoconstriction induced by eucapnic hyperpnea with cold air is a function of the route of administration of atropine. In six subjects with asthma, we constructed dose-response curves to inhaled methacholine and to eucapnic hyperpnea with cold air after treatment with inhaled atropine (0.5 mg delivered) and intravenous placebo, with inhaled placebo and intravenous atropine (0.5 mg injected), and with inhaled and intravenous placebos. Atropine by either route shifted the dose-response curves to both cold air and to methacholine to the right. In every subject, however, inhaled atropine caused a markedly greater rightward shift of the inhaled methacholine dose-response curve than did intravenous atropine, whereas inhaled and intravenous atropine had similar effects on the cold air dose-response curve. These findings suggest that the apparent disparity between the doses of atropine required to inhibit methacholine- and cold air-induced bronchoconstriction may be a function of the route of administration of atropine and thus does not imply a nonmuscarinic action of atropine. The findings support the view that cold air causes bronchoconstriction via muscarinic pathways.     

Effect of exercise on nonspecific airway reactivity in asthmatics

To investigate whether exercise increases the responsivity of the tracheobronchial tree to nonspecific stimuli, 11 atopic asthmatics underwent serial challenges with aerosolized methacholine before and 4 and 24 h after an asthma attack induced by cycle ergometry while breathing cold air (mean +/- SE = -11 +/- 1 degree C). Bronchodilator therapy was withheld the day before and throughout each study day. There were no significant differences in base-line lung function before exercise or any of the three methacholine bronchoprovocations. Exercise produced a 25 +/- 3% maximal fall in 1-s forced expiratory volume (FEV1) within 15 min. This attack was not associated with either an immediate or a delayed increase in methacholine sensitivity. The provocation concentration of methacholine required to reduce the FEV1 20% from saline control at base line and 4 and 24 h after exercise were 0.8 +/- 0.5, 0.9 +/- 0.5, and 1.1 +/- 0.8 mg/ml, respectively. This was not significant by a one-way analysis of variance (F = 0.078, P = NS). These data demonstrate that exercise-induced asthma does not produce an increase in nonspecific bronchial reactivity. Hence, if mediators are elaborated with exercise as has been suggested, they appear to function differently than when released by antigen.     

Effects of bronchoconstriction on respiratory muscle activity during expiration

The effect of methacholine-induced bronchoconstriction on the electrical activity of respiratory muscles during expiration was studied in 12 anesthetized spontaneously breathing dogs. Before and after aerosols of methacholine, diaphragm, parasternal intercostal, internal intercostal, and external oblique electromyograms were recorded during 100% O2 breathing and CO2 rebreathing. While breathing 100% O2, five dogs showed prolonged electrical activity of the diaphragm and parasternal intercostals in early expiration, postinspiratory inspiratory activity (PIIA). Aerosols of methacholine increased pulmonary resistance, decreased tidal volume, and elevated arterial PCO2. During bronchoconstriction, when PCO2 was varied by CO2 rebreathing, PIIA was shorter at low levels of PCO2, and external oblique and internal intercostal were higher at all levels of PCO2. Vagotomy shortened PIIA in dogs with prolonged PIIA. After vagotomy, methacholine had no effects on PIIA but continued to increase external oblique and internal intercostal activity at all levels of PCO2. These findings indicate that bronchoconstriction influences PIIA through a vagal reflex but augments expiratory activity, at least in part, by extravagal mechanisms.     

Short-term potentiation of breathing in humans.

The purpose of this study was to determine if the increase in ventilation induced by hypoxic stimulation of the carotid bodies (CB) persists after cessation of the stimulus in humans. I reasoned that a short-term potentiation (STP) of breathing, sometimes called an "afterdischarge," could be unmasked by combining hypoxia with exercise, because ventilation increases synergistically under these conditions. Seven young healthy men performed mild bicycle exercise (30% peak power) while breathing O2 for 1.5 min ("control" state), and their CB were then stimulated by 1.5 min of hypoxic exercise (10% O2--balance N2). CB stimulation was then terminated by changing the inspirate back to O2 as exercise continued. Inspiratory and expiratory duration (TI and TE) and inspiratory flow and its time integral [tidal volume (VT)] were measured with a pneumotachometer. Inspired minute ventilation (VI) and mean inspiratory flow (VT/TI) declined exponentially after the cessation of CB stimulation, with first-order time constants of 28.6 +/- 6.7 and 24.6 +/- 1.6 (SD) s, respectively. The slow decay of VI was due primarily to potentiation of both TI and TE, although the effect on the latter predominated. Additional experiments in six subjects showed that brief intense CB stimulation with four to five breaths of N2 during mild exercise induced STP of similar magnitude to that observed in the hypoxic exercise experiments. Finally, the imposition of hyperoxia during air breathing exercise at a level of respiratory drive similar to that induced by the hypoxic exercise did not change VI significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of induced bronchoconstriction on pulmonary blood flow

Allergic bronchoconstriction may be associated with hemodynamic alterations due to changes in respiratory mechanics (or the associated changes in arterial blood gas composition) or the cardiovascular effects of chemical mediators. In an attempt to differentiate between these two possible mechanisms, we obtained measurements of hemodynamics, respiratory mechanics, and O2 consumption (VO2) in nine asymptomatic adult ragweed asthmatics before and after inhalation challenge with either ragweed extract or methacholine. We measured specific airway conductance (sGaw) by body plethysmography, pleural pressure with an esophageal balloon catheter, pulmonary blood flow (Q) and VO2 by a rebreathing technique, and heart rate. For a similar degree of bronchoconstriction after the two types of challenge (mean +/- SD sGaw 0.06 +/- 0.03 and 0.05 +/- 0.02 cmH2O-1 . s-1, P = NS), mean Q increased by 29 and 29%, and mean VO2 by 33 and 37% 15-20 min after ragweed and methacholine, respectively. Since heart rate did not change, there was a concomitant increase in mean stroke volume by 25 and 35%, respectively (P less than 0.05). The respiratory pleural pressure swings during quiet breathing and the rebreathing maneuver and the work of breathing during rebreathing also increased to a similar degree after the two types of challenge. These observations suggest that, if chemical mediators are released into the circulation during antigen-induced bronchoconstriction, their blood concentrations are too low for appreciable cardiovascular effects. The increase in rebreathing cardiac output during allergic and nonallergic bronchoconstriction is probably due to increases in intrathoracic pressure swings and in the work of breathing.     

Partitioning of nasal and pulmonary resistance changes during noninvasive plethysmography in mice

Double-chamber plethysmography is a well established noninvasive method of assessing airflow obstruction in small lab animals. It allows measurement of the specific airway resistance (sRaw), which unlike enhanced pause (Penh), is a meaningful airway mechanics parameter. Since sRaw is measured in spontaneously breathing mice, a limitation of the method is the inability to exclude nasal resistance changes. We recently showed that mice are not truly obligate nasal breathers and that after nasal occlusion, nasally breathing mice can transition to an oral mode of breathing. We now show that it is experimentally possible to algebraically separate the average nasal and pulmonary (including laryngeal) components of total airway resistance change by a series of measurements made across groups of mice breathing nasally or orally, assuming that oral resistance remains constant. Using this approach, we show that nasal resistance change comprises one-half or more of the total resistance change during methacholine challenge. Inhibition of mucin secretion from airway goblet cells attenuates pulmonary but not nasal airway hyperresponsiveness (AHR), and nasal AHR in a murine model of rhinitis may be related to edema.     

Urinary leukotriene E4 excretion in exercise-induced asthma.

Recent evidence suggests that the cysteinyl-leukotrienes (LTC4, LTD4, and LTE4) may be important in the pathogenesis of exercise-induced asthma. To evaluate the role of these mediators further, nine asthmatic subjects with exercise-induced bronchoconstriction were studied on two occasions. On visit 1, subjects performed 6 min of treadmill exercise; the mean maximal percent fall in FEV1 was 38.0 +/- 5.3%. On visit 2, maximal bronchoconstriction observed after exercise was matched with aerosolized methacholine. Urine was collected in two 90-min fractions (0-90 and 90-180 min) after challenges and analyzed by high-performance liquid chromatography-radioimmunoassay for LTE4. There were no significant differences in urinary LTE4 excretion between exercise and methacholine challenges for the periods 0-90 min (16.9 +/- 5.4 vs. 20.4 +/- 4.2 ng/mmol urinary creatinine), 90-180 min (24.9 +/- 8.2 vs. 20.1 +/- 5.5), or 0-180 min (21.5 +/- 6.5 vs. 18.8 +/- 4.1). Thus in contrast to allergen-induced bronchoconstriction, there is little evidence for enhanced cysteinyl-leukotriene generation in exercise-induced bronchoconstriction as assessed by urinary LTE4. If local release and subsequent participation of functionally active cysteinyl-leukotrienes in the pathways that ultimately lead to bronchoconstriction after exercise challenge do occur, these are of insufficient magnitude to perturb urinary LTE4 excretion.     

Laryngeal constriction in normal humans during experimentally induced bronchoconstriction

Changes in the size of the glottis with bronchoconstriction were assessed in six normal subjects following inhalation of histamine or methacholine. Measurements were made during both tidal breathing and panting at 2-3 Hz. The midexpiratory size of the glottis was decreased by a mean of 8% during bronchoconstriction compared with control during tidal breathing. Changes in midinspiratory size were inconsistent. During panting, the glottic size was unchanged from inspiration to expiration but decreased in 7 of 15 studies during bronchoconstriction. The decreases in expiratory size of the glottis during quiet breathing would lead to an elevated laryngeal resistance coupled with an increased lower airway resistance. Although this seems to be a paradoxical laryngeal response, it may contribute to maintaining hyperinflation during bronchoconstriction, thereby effectively enlarging the lower airways.     

Exercise endurance and arterial desaturation in normobaric hypoxia with increased chemosensitivity

We studied whether exercise endurance under normobaric hypoxia can be enhanced by increasing hypoxic ventilatory sensitivity with almitrine bismesylate (ALM). On both ALM and placebo (PL) days, resting subjects breathed a hypoxic gas mixture (an inspired O2 fraction of 10.4-13.2%), which lowered resting arterial O2 saturation (SaO2) to 80%. After 15 min of rest there was a 3-min warm-up period of exercise at 50 W (light) on a cycle ergometer, followed by a step increase in load to 60% of the previously determined maximum power output with room-air breathing (moderate), which was maintained until exhaustion. With PL, SaO2 decreased rapidly with the onset of exercise and continued to fall slowly during moderate exercise, averaging 71.0 +/- 1.8% (SE) at exhaustion. With ALM, saturation did not differ from PL during air breathing but significantly exceeded SaO2 with PL, by 3.4% during resting hypoxia, by 4.0% at the start of exercise, and by 5.9% at exhaustion. Ventilation was not affected by ALM during air breathing and was slightly, although not significantly, increased during hypoxic rest and exercise. ALM was associated with an increased heart rate during room air breathing but not during hypoxia. Endurance time was 20.6 +/- 1.6 min with ALM and 21.3 +/- 0.9 min with PL. During hypoxic exercise, the potential benefit of greater saturation with ALM is apparently offset by other unidentified factors.     

Combined effects of ozone exposure and ambient heat on exercising females

Ten aerobically trained young adult females exercised continuously at 66% of maximum O2 uptake for 1 h while exposed orally to filtered air and 0.15 and 0.30 parts per million (ppm) ozone (O3) in both moderate (24 degrees C) and hot (35 degrees C) ambient conditions. Exposure to 0.30 ppm O3 induced significant impairment in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1.0), and other pulmonary function variables. Exercise respiratory frequency (fR) increased, whereas tidal volume and alveolar volume (VA) decreased with 0.30 ppm O3 exposure. Significant interactions of O3 and ambient heat were obtained for fR and VA, whereas FVC and FEV1.0 displayed a trend toward an O3-temperature interaction. Although expired ventilation increased, the interactions could not be ascribed to a greater O3 effective dose in the 35 degrees C exposures. However, subjective discomfort increased with both O3 and heat exposure such that three subjects ceased exercise prematurely when O3 and ambient heat were combined. We conclude that accentuation of subjective limitations and certain physiological alterations by ambient heat coinciding with photochemical oxidant episodes is likely to result in more severe impairment of exercise performance, although the mechanisms remain unclear.     

Effects of NO2 alone and in combination with O3 on young men and women

Previous studies of 2 h of exposure to NO2 at high urban atmospheric levels (i.e., 0.50-1.0 ppm), utilizing light-to-moderate exercise for up to 1 h have failed to demonstrate significant pulmonary dysfunction in healthy humans. To test the hypothesis that heavy sustained exercise would elicit pulmonary dysfunction on exposure to 0.60 ppm NO2 and/or enhance the effects of exposure to 0.30 ppm O3, 40 aerobically trained young adults (20 males and 20 females) completed 1 h of continuous exercise at work rates eliciting a mean minute ventilation of 70 and 50 l/min for the males and females, respectively. Exposures to filtered air, 0.60 ppm NO2, 0.30 ppm O3, and 0.60 ppm NO2 plus 0.30 ppm O3 were randomly delivered via an obligatory mouthpiece inhalation system. Treatment effects were assessed by standard pulmonary function tests and exercise ventilatory and subjective symptoms response. Two-way analysis of variance with repeated measures and post hoc analyses revealed a statistically significant (P less than 0.05) effect of O3 on forced expiratory parameters, specific airway resistance, exercise ventilatory response, and reported subjective symptoms of respiratory discomfort. In contrast, no significant effect of NO2 was observed nor was there any significant interaction of NO2 and O3 in combination. There were no significant differences between male and female responses to gas mixture treatments. It was concluded that inhalation of 0.60 ppm NO2 for 1 h while engaged in heavy sustained exercise does not elicit effects evidenced by measurement techniques used in this study nor evoke additive effects beyond those induced by 0.30 ppm O3 in healthy young adults.     

Changes in breathing pattern at loads near perceptual threshold at different work levels

Five subjects were tested to determine the threshold for detection of an added resistance to inspiration in three tests, one at rest and two with exercise (mild = 50 W; moderate = 100 W) on a cycle ergometer. Changes in the breathing pattern were examined at added resistances near the perceptual threshold. Added inspiratory resistances with a 50% probability of detection were very variable at rest; they decreased significantly from rest (250 Pa.l-1.s-1) to moderate exercise (98 Pa.l-1.s-1) in four subjects. It is suggested that physical exercise may cause discomfort even when workers wearing a respirator do not have any abnormal sensation during sedentary work. Breathing patterns were compared between resistance loaded and unloaded breathing during each test. Decreases in inspiratory peak flow and acceleration of flow early in inspiration were found in resistance loaded breathing in almost all tests and a tendency for tidal volume to decrease was found during moderate exercise only. The ratios of resistance loaded to unloaded breathing for inspiratory time (ti) and total time (tt) tended to be greater in the detected than in the undetected responses at rest and during mild exercise but not during moderate exercise. This would imply that further prolongation of ti and tt in the detected responses was attributable to conscious or subconscious aspects of the resistance leading responses: however, these adjustments in breathing, which reduce frequency, would be less likely to occur as the work rate increases.