Acetazolamide can be taken at sea level to prevent acute mountain sickness during subsequent altitude exposure. Acetazolamide causes metabolic acidosis at sea level and altitude, and increases S a O 2 (arterial oxygen saturation) at altitude. The aim of the present study was to determine whether acetazolamide impairs muscle endurance at sea level but not simulated altitude (4300 m for <3 h). Six subjects (20±1 years of age; mean±S.E.M.) performed exhaustive constant work rate one-leg knee-extension exercise (25±2 W) once a week for 4 weeks, twice at sea level and twice at altitude. Each week, subjects took either acetazolamide (250 mg) or placebo orally in a double-blind fashion (three times a day) for 2 days. On day 2, all exercise bouts began approx. 2.5 h after the last dose of acetazolamide or placebo. Acetazolamide caused similar acidosis (pH) in all subjects at sea level (7.43±0.01 with placebo compared with 7.34±0.01 with acetazolamide; P <0.05) and altitude (7.48±0.03 with placebo compared with 7.37±0.01 with acetazolamide; P <0.05). However, endurance performance was impaired with acetazolamide only at sea level (48±4 min with placebo compared with 36±5 min with acetazolamide; P <0.05), but not altitude (17±2 min with placebo compared with 20±3 min with acetazolamide; P =not significant). In conclusion, lack of impairment of endurance performance by acetazolamide compared with placebo at altitude was probably due to off-setting secondary effects resulting from acidosis, e.g. ventilatory induced increase in S a O 2 for acetazolamide compared with placebo (89±1 compared with 86±1% respectively; P <0.05), which resulted in an increased oxygen pressure gradient from capillary to exercising muscle.

Acute mountain sickness (AMS) commonly occurs at altitudes exceeding 2000–2500 m and usually resolves after acclimatization induced by a few days of chronic residence at the same altitude. Increased ventilation and diuresis may contribute to the reduction in AMS with altitude acclimatization. The aim of the present study was to examine the effects of intermittent altitude exposures (IAE), in combination with rest and exercise training, on the incidence and severity of AMS, resting ventilation and 24-h urine volume at 4300 m. Six lowlanders (age, 23±2 years; body weight, 77±6 kg; values are means±S.E.M.) completed an Environmental Symptoms Questionnaire (ESQ) and Lake Louise AMS Scoring System (LLS), a resting end-tidal partial pressure of CO 2 ( P ETCO 2 ) test and a 24-h urine volume collection at sea level (SL) and during a 30 h exposure to 4300 m altitude-equivalent (barometric pressure=446 mmHg) once before (PreIAE) and once after (PostIAE) a 3-week period of IAE (4 h·day -1 , 5 days·week -1 , 4300 m). The previously validated factor score, AMS cerebral score, was calculated from the ESQ and the self-report score was calculated from the LLS at 24 h of altitude exposure to assess the incidence and severity of AMS. During each IAE, three subjects cycled for 45–60 min·day -1 at 60–70% of maximal O 2 uptake ( V O 2 max) and three subjects rested. Cycle training during each IAE did not affect any of the measured variables, so data from all six subjects were combined. The results showed that the incidence of AMS (%), determined from both the ESQ and LLS, increased ( P <0.05) from SL (0±0) to PreIAE (50±22) at 24 h of altitude exposure and decreased ( P <0.05) from PreIAE to PostIAE (0±0). The severity of AMS (i.e. AMS cerebral symptom and LLS self-report scores) increased ( P <0.05) from SL (0.02±0.02 and 0.17±0.17 respectively) to PreIAE (0.49±0.18 and 4.17±0.94 respectively) at 24 h of altitude exposure, and decreased ( P <0.05) from PreIAE to PostIAE (0.03±0.02 and 0.83±0.31 respectively). Resting P ETCO 2 (mmHg) decreased (i.e. increase in ventilation; P <0.05) from SL (38±1) to PreIAE (32±1) at 24 h of altitude exposure and decreased further ( P <0.05) from PreIAE to PostIAE (28±1). In addition, 24-h urine volumes were similar at SL, PreIAE and PostIAE. In conclusion, our findings suggest that 3 weeks of IAE provide an effective alternative to chronic altitude residence for increasing resting ventilation and reducing the incidence and severity of AMS.

Augmentation of circulating noradrenaline concentration stimulates ventilation during the initial stages of exercise and this is accompanied by an increased sensation of dyspnoea and exertion. This previous study [Clark, Galloway, MacFarlane, Henderson, Aitchison and McMurray (1997) Eur. Heart J. 18, 1829–1833] suggested a link between dyspnoea, which commonly limits exercise tolerance in heart failure patients, and high circulating noradrenaline concentration in these patients. The present study investigated this relationship further using sympathetic inhibition. Ten healthy normotensive males performed 10 min of submaximal cycling exercise at approx. 70% of maximal oxygen uptake per min ( Vċ O 2max ) on three occasions one week apart. The first of these sessions was a familiarization session and the other two were experimental study days. On each of the study days, subjects attended the laboratory in the morning after an overnight fast and, following a resting blood sample, were administered placebo or moxonidine (0.4 mg) in a double blind cross-over design. After a 90-min absorption period, subjects undertook the exercise task. Blood was drawn, expired gas was analysed breath by breath, blood pressure, heart rate and ratings of perceived dyspnoea and exertion were obtained. Moxonidine treatment significantly reduced plasma noradrenaline concentration ( P < 0.01), mean arterial pressure ( P < 0.01), and blood glycerol concentration ( P < 0.05), but no differences were observed in heart rate, the ventilatory response to exercise or subjective ratings of dyspnoea and exertion. This study indicates that reducing sympathetic activity does not affect ventilation, perceived dyspnoea or perceived exertion in normotensive males. Therefore it can be concluded that reducing sympathetic activity may not be an appropriate strategy to help reduce perceived dyspnoea.

1. Ventilation was measured during normoxia, hypoxia and hypercapnia before and after administration of almitrine in conscious, unrestrained, tracheostomized rats with the superior laryngeal nerves intact or cut. In superior laryngeal nerve-intact animals breathing air, almitrine increased minute ventilation due to an increase in respiratory frequency with no change in tidal volume. In superior laryngeal nerve-sectioned animals, the minute ventilatory response to almitrine was reduced due to a reduced tidal volume component of the response. Almitrine increased the ventilatory response to hypercapnia in superior laryngeal nerve-intact but not in sectioned animals. 2. In anaesthetized, vagotomized rats breathing spontaneously through a low-cervical tracheostomy, diaphragm and geniohyoid electromyographic activities were recorded. Arterial blood pressure and rectal temperature were continuously monitored. A single dose of almitrine was administered intravenously. In all animals, the geniohyoid muscle had phasic inspiratory activity which slightly preceded diaphragm activity. Almitrine had no effect on respiratory frequency or inspiratory and expiratory duration but increased mean peak integrated diaphragm (+29.3 ±13.6%) and geniohyoid (+ 132.0 ±21.3%) muscle activity. 3. These results show that almitrine exerts part of its ventilatory effects through superior laryngeal nerve afferents. Almitrine preferentially excites upper airway compared with diaphragm muscle activity, suggesting a potential role in the alleviation of obstructive apnoea.

1. Fenspiride is an anti-inflammatory agent that may have a role in reversible obstructive airways disease. Small, but significant, improvements have been seen in airways function and arterial oxygen tension in patients with mild chronic obstructive pulmonary disease. These changes have been attributed to the anti-inflammatory properties of the drug. However, airways function can be improved by other means, e.g. improved ventilation/perfusion ratio or reduced airways resistance. The possibility that fenspiride may have actions other than anti-inflammatory was investigated in two animal species. 2. In the rat, actions on the pulmonary circulation were investigated in the isolated perfused lung, but fenspiride proved to be a poor pulmonary vasodilator, showing only a small reversal of the raised pulmonary artery pressure induced by hypoxia. 3. Ventilation was measured in the anaesthetized rat using whole-body plethysmography. Fenspiride caused no increase in ventilation or changes in arterial blood gases. However, a profound hypotensive action was observed with high doses. 4. The possibility that a decrease in airways resistance ( R aw ) might occur with fenspiride was investigated in anaesthetized guinea pigs. Capsaicin (30 μmol/l) was used to increase baseline R aw through bronchoconstriction. Fenspiride gave a dose-dependent partial reversal of the raised R aw , and its administration by aerosol proved as efficacious as the intravenous route. In addition, the hypotensive side-effect found with intravenous injection was alleviated by aerosolized fenspiride. 5. An anti-bronchoconstrictor action of fenspiride could be one of the mechanisms involved in improving airways function and P ao 2 , seen in mild chronic obstructive pulmonary disease.

1. Maximal exercise capacity in cystic fibrosis is influenced by both pulmonary and nutritional factors: lung disease by limiting maximal achievable ventilation, and malnutrition through a loss of muscle mass. The associated reduction in everyday activities may result in peripheral muscle deconditioning. 2. We studied 14 stable patients with cystic fibrosis (six males, eight females) and 14 healthy control subjects (seven males, seven females) in order to assess the influence of these factors on exercise performance. Subjects underwent anthropometry to estimate muscle mass, spirometry to assess ventilatory capacity, a 30 s sprint on an isokinetic cycle ergometer to assess maximal leg muscle performance, and progressive cycle ergometry to assess overall exercise capacity. 3. Compared with control subjects, the patients with cystic fibrosis were of similar age and height but weighed proportionately less [% ideal weight (mean ± sd ): 94.3 ± 9.64 versus 109.5 ± 11.82] and showed evidence of airflow limitation [forced expiratory volume in 1.0s (FEV 1.0 ) 72.5 ± 24.78 versus 112.6 ± 14.25% of predicted]. 4. The patients with cystic fibrosis did less absolute (5.1 ± 1.89 versus 7.3 ± 1.97 kJ) but similar relative maximal (11.5 ± 3.41 versus 13.1 ± 3.55 kJ/kg lean body mass) sprint work. During progressive exercise, the group with cystic fibrosis achieved lower absolute [maximal O 2 consumption ( V o 2 max.) 1.8 ± 0.527 versus 3.0 ± 0.655 litres/min] and relative ( V o 2 max./kg lean body mass: 40.5 ± 9.23 versus 53.0 ± 11.62 ml min −1 kg −1 ) work levels. 5. Step-wise linear regression was carried out with V o 2 max. as the dependent variable and lean body mass, FEV 1.0 and 30 s sprint work as independent variables. V o 2 max. was best accounted for by a two-factor equation with FEV 1.0 and 30 s sprint work ( r 2 = 0.882), with FEV 1.0 being relatively more important. 6. While noting the importance of lung disease as a limiting factor, these results suggest that peripheral muscle function is a more sensitive determinant of maximal performance than lean body mass. The 30 s sprint work results imply that the effects of mild malnutrition in cystic fibrosis are quantitative, affecting the size of the muscle mass but not the performance of the remaining muscle.

1. To examine the relationship between eucapnic morbid obesity and ventilatory responsiveness to chemical stimuli, we measured hypercapnic and hypoxic ventilatory responses in 29 patients (26 women, three men) before and 3–6 months after gastroplasty. No subject demonstrated resting awake hypercapnia and none suffered from sleep-disordered breathing. 2. Mean weight fell significantly (122.8 ± 21.4 vs 102.2 ± 22.8 kg, P <0.0001) and functional residual capacity rose slightly but significantly (1.94 ± 0.58 vs 2.18 ± 0.64 litres; P <0.05) after weight loss. 3. The hypercapnic ventilatory response slope fell significantly after weight loss (2.88 ± 2.27 vs 2.24 ± 1.06 litres min −1 mmHg −1 , P <0.05) with a significant shift of the ventilatory response curve to the right. There were no statistically significant changes in the patterns of ventilatory response. 4. In addition, isocapnic hypoxic ventilatory response slopes, measured at two levels of carbon dioxide partial pressure, fell significantly after weight loss. These changes were accompanied by significant shifts of the ventilatory response curves to the left, such that, for a given oxygen saturation, mean ventilation was significantly lower in the less obese state. Similarly to hypercapnic responses, there were no statistically significant changes in ventilatory pattern despite the changes in overall ventilatory response. 5. We conclude that ventilatory responsiveness to chemical simuli is increased in obese subjects who maintain adequate alveolar ventilation while awake.

1. The subjective changes accompanying alterations in inspired oxygen concentration during heavy exercise have been investigated single blind, in normal subjects. 2. In particular, the intensity of the sensation of breathlessness was quantified using a visual analogue scale and changes were compared with those in objective ventilatory measures. 3. Eleven subjects performed three steady-state workload exercise tests on different days and 100% O 2 , 15% O 2 or air were randomly administered for a fixed interval during each test. 4. Compared with air breathing, all subjects felt less breathless during 100% O 2 breathing, and ten of them felt more breathless when inspiring 15% O 2 ; these changes were reversed on return to air breathing. 5. During and after 100% O 2 , the time course of changes in breathlessness was similar to those for ear arterial oxygen saturation and minute ventilation such that it could be a secondary response to either. However, during and after inspiration of 15% O 2 , changes in breathlessness occurred relatively more quickly than those in ventilation, more closely reflecting changes in oxygen saturation; this suggests that hypoxia, per se , could contribute to the genesis of this sensation. 6. Individual variability in breathlessness responses to exercise and changes in inspired oxygen concentration did not correlate with objective ventilatory changes; neither were changes in breathlessness in the group particularly associated with changes in respiratory frequency or tidal volume.

1. Continuous recordings of arterial pH, ventilation, airway CO 2 and heart rate were made during rest and during 3–4 min periods of rhythmic leg exercise in four renal patients with arteriovenous shunts. 2. The patients were anaemic (haemoglobin 6.5–9.0 g/dl) but had a normal ventilatory response to exercise as judged by the ratio of the change in ventilation to the change in CO 2 production. 3. Breath-by-breath oscillations in arterial pH disappeared for the majority of the exercise period in each patient. 4. Changes in mean arterial pH and end-tidal CO 2 tension with exercise were inconsistent between subjects but consistent within a given subject. On average, mean arterial pH rose by 0.011 pH unit. Changes in end-tidal CO 2 tension reflected changes in mean pHa by falling on average by 1 mmHg (0.13 kPa). 5. Hypercapnia and acidaemia were not found to be necessary for the ventilatory response to moderate exercise.

1. Six patients with chronic airflow limitation rebreathed CO 2 . Subsequently they voluntarily copied their stimulated breathing pattern while normocapnia was maintained. On a separate occasion four of these patients performed progressively increasing exercise and later copied these breathing patterns. 2. During all experiments flow, ventilation and pleural pressures were recorded. In addition, breathlessness was measured on a visual analogue scale every 30 s. 3. In these patients voluntary copying of either form of stimulated breathing resulted in diminished breathlessness and in some cases in complete abolition of the sensation, despite similar levels and patterns of ventilation in the two situations. 4. No systematic or consistent differences in the mechanics of breathing between stimulated and voluntarily copied breathing were found. 5. There was no correlation found between breathlessness score and any mechanical variable measured. 6. These results show that despite similarity in mechanics between stimulated and voluntary hyperventilation, the sensation of breathlessness is much diminished during the latter in these patients. This suggests that the sensation of breathlessness is more dependent upon the awareness of central processing than upon input from peripheral mechanoreceptors.

1. To investigate whether changes in P a co 2 can be detected independently of the CO 2 -induced changes in pulmonary ventilation, we tested five normal subjects for the ability to distinguish different levels of end-tidal P co 2 ( P ET co 2 ) while holding minute ventilation constant. 2. Helped by a visual feedback system, the subjects maintained a constant ventilation targeted at a level that was higher than that dictated by the chemical drive at P ET co 2 = 50 mmHg (6.7 kPa). End-tidal P co 2 was held at 40 mmHg (5.3 kPa) during the first 2 min of each test trial ('control period'); then, for 4 min ('test period'), P ET co 2 was either elevated to 50 mmHg or kept at 40 mmHg. Twelve runs were performed by each subject. 3. In 24 out of the total 30 trials (80%) in which P ET co 2 was raised during the test period to 50 mmHg, the subjects detected the changes. There was one false positive result (3%), when P ET co 2 kept at 40 mmHg during the test period was reported as different from control. In four out of the five subjects the ability to detect the change in P ET co 2 from 40 to 50 mmHg was statistically significant. 4. We conclude that increases in P ET co 2 can be detected independently of changes in the absolute level of ventilation.

1. Rapid steady-state CO 2 responses were determined in six normal subjects at rest and five subjects at four different work loads up to 125 W, by injecting pure CO 2 at constant flow into a small mixing chamber in the inspiratory limb of a breathing circuit. 2. The time course of the response of ventilation ( V ) and mean alveolar P co 2 ( P aco 2 ) was checked in separate experiments, where the flow rate of injected CO 2 was changed abruptly and the effects were followed for 10 min. 3. V and P aco 2 were measured every breath, and the results ensemble-averaged for each subject (two or three runs per subject) and then for the groups as a whole, in 30 s or 60 s time bins. 4. P aco 2 during exercise was estimated by graphical reconstruction from the sloping alveolar plateau, and separately by the empirical equation of Jones, Robertson & Kane [1]. At rest, P aco 2 was assumed equal to end-tidal P co 2 ( P et co 2 ). 5. With the constant inflow technique, 4 min was required to reach steady-state V and P aco 2 during exercise, and 6 min at rest. 6. At rest, with 4 min steps (doubtful steady state) the averaged CO 2 response was concave up. With 6 min steps the response was almost linear. In neither case was the deviation from linearity statistically significant. 7. During exercise, the averaged CO 2 responses were essentially isocapnic at work loads greater than 75 W with either method of deriving P aco 2 .

1. Nine patients with chronic obstructive airways disease performed a 6 min self-paced walk (breathing air) on a treadmill and then identical (but operator-controlled) treadmill walks breathing either air or supplemental oxygen sufficient to just prevent arterial oxygen desaturation during the exercise. 2. During the exercises, ventilation was recorded and patients recorded their sensation of breathlessness on a visual analogue scale (VAS) every 30 s. 3. Breathing supplemental oxygen produced a small fall in mean exercise ventilation and a large and consistent reduction in mean exercise breathlessness. In seven patients the VAS scores were higher on air than with supplemental oxygen, at similar levels of ventilation. An analysis of co-variance, to control for reduction in ventilation, showed a decrease in mean breathlessness when breathing supplemental oxygen, significant at the 8% level. 4. The reduction in breathlessness produced by preventing exercise desaturation cannot be explained by the decrease in ventilation. This suggests that hypoxia may be a stimulus for breathlessness. The mechanism is unknown.

1. Rapid steady-state CO 2 responses were determined in five normal adults at rest and at up to six levels of exercise by injecting pure CO 2 at a constant flow into the inspiratory limb of a breathing circuit. 2. Ventilation ( V ) was measured with a dry gas meter and Pco 2 at the mouth was recorded by a mass spectrometer. Mean alveolar P co 2 ( P aco 2 ) was taken as equal to end-tidal P co 2 at rest, and during exercise was derived graphically from the sloping alveolar plateaus. The accuracy of the latter method was checked in separate experiments against arterial P co 2 ( P a co 2 ). 3. The mean results showed a linear relationship between change in P aco 2 and change in V for work loads ranging from rest to 75 W ( r = 0.94–0.98). Above 75 W the response became concave down with an initial essentially isocapnic phase. 4. This suggests that during exercise there is a large increase in CO 2 sensitivity about the control point.

1. Almitrine bismesylate (5–10 μg/kg) was given as an intravenous bolus to anaesthetized, paralysed dogs (a) with closed-chest ( n = 5) and (b) with open-chest ( n = 7) in whom the retrocardiac lobe was separately ventilated. Pulmonary, lobar and systemic haemodynamics were measured under hypoxic, normoxic and hyperoxic conditions. Total pulmonary blood flow was measured by thermodilution and lobar flow by electromagnetic flow meter. 2. In the closed-chest preparations, almitrine caused an increase in pulmonary vascular resistance (PVR) at all levels of inspired oxygen, the increments being 82% (30% O 2 ), 91% (air) and 9% (13% O 2 ). The control PVR varied inversely with arterial P o 2 but there was no significant interaction between the almitrine and hypoxia induced vasoconstriction with multiple linear regression analysis. 3. In the open-chest preparations, PVR and lobar vascular resistance (LVR) increased after almitrine by 48% and 41% respectively when both lung and lobe inspired 30% O 2 . When the lobe was switched to 12.5% O 2 or nitrogen (lung inspiring 30%) PVR again increased (+ 52%) after almitrine but LVR decreased in five of seven lobes (lobar flow increasing despite constant cardiac output), the overall change being − 4%. Analysis of covariance showed that the lobar response to almitrine was significantly different under hypoxic conditions compared with hyperoxic ( P < 0.05). 4. With ventilation maintained constant, there was no significant change in arterial P o 2 after almitrine in any experimental condition. 5. In conclusion, almitrine is generally a pulmonary vasoconstrictor but can dilate vessels when they are constricted by local hypoxia. Almitrine does not enhance local hypoxic vasoconstriction in the dog.

1. In seven normal subjects the ventilatory responses to progressive isocapnic hypoxia and hyperoxic hypercapnia were measured during rebreathing. 2. During an infusion of somatostatin (10 nmol/mm) the mean hypoxic response decreased by 66% (control: − 1.6 sd 1.2 litres min −1 % −1 S ao 2 : somatostatin: − 0.6 sd 0.7) but the mean hypercapnic response was unchanged (control: 2.0 sd 0.8 litre min −1 mmHg −1 ; somatostatin: 2.3 sd 1.2). There was no change in resting V ˙ O 2 or V ˙ CO 2 during somatostatin infusion. 3. The opiate antagonist, naloxone (0.1 mg/kg, intravenously), caused little change in either response (mean hypoxic response: − 1.7 sd 1.0 litre min −1 % −1 S ao 2 ; mean hypercapnic response: 2.4 sd 0.9 litre min −1 mmHg −1 ). 4. In five of the subjects the dopamine antagonist, prochlorperazine (10 mg, intravenously), increased the mean hypoxic response by 134% (control: − 1.9 sd 1.4 litres min −1 % −1 S ao 2 ; after prochlorperazine: − 3.8 sd 1.6; P < 0.05). The mean hypercapnic response after this drug was also increased (control: 2.1 sd 1.0 litre min −1 mmHg −1 ; after prochlorperazine: 3.1 sd 1.0) but this change did not achieve significance. 5. The selective effect of somatostatin on the hypoxic response, suggestive of an action on the carotid body, was not inhibited by prior injection of either naloxone or prochlorperazine, and its mode of action remains to be found.

1. We have examined the hypothesis that hypoxaemia contributes to breathlessness by a mechanism distinct from its action as a ventilatory stimulant. 2. Five patients who developed arterial oxygen desaturation during incremental exercise were studied. Exercise tests were performed on a cycle-ergometer. Breathlessness was measured by using a visual analogue scale technique. All five patients had considerable previous experience of these procedures. 3. Two identical exercise tests were performed by each patient, breathing either room air or 60% oxygen in a blind randomized study. 4. Breathing air, arterial saturation at rest was 93% and fell by 7% during exercise. Breathing 60% oxygen, resting saturation was 98% and there was no fall during exercise. 5. Breathing oxygen, ventilation for a given work load was reduced and exercise duration was increased when compared with air breathing. 6. In each of the five patients the relationship between breathlessness and minute ventilation was the same whether breathing air or 60% oxygen, despite the reduction in ventilation for a given work rate.

1. Submaximal bicycle exercise tests have been performed in nine healthy men on seven annual occasions between the ages of 64 and 70 years. Ten younger men (average age 33 years) have also been studied once for comparison. 2. The ventilatory cost of submaximal work at V̇ o 2 = 1 litre/min rises significantly from 24.3 ±0.8 litres/min at age 64 years to 31.8 ± 1.8 litres/min at age 70 years; the latter value differs significantly from that of the young men (25.6 ± 0.9 litres/min). Similar changes are seen in the ventilation at 75 W and at V̇ co 2 = 1 litre/min. The rate of change, between 3% and 5% per year, is considerably greater than that found for the change with age in cross-sectional studies of younger men. There is also a rise in the respiratory quotient, consistent with the hyperventilation found. 3. The cardiac frequency at 1 litre/min also rose with age in the older men, and rough estimates of the decline in their aerobic capacity suggest that progressive anaerobiosis could account for at least some of this increase in ventilation seen during submaximal work.

1. To determine the mode of action of doxapram in man we have measured ventilation, oxygen uptake, CO 2 production, hypoxic and hypercapnic ventilatory responses in six healthy men before and during intravenous infusion to maintain a constant plasma level. 2. Doxapram changed neither resting oxygen uptake nor CO 2 production but produced a substantial increase in resting ventilation at both levels of end-tidal CO 2 studied. 3. Doxapram increased the ventilatory response to isocapnic hypoxia from − 0.8 ± 0.4 litre min −1 (% S a o 2 ) −1 to −1.63 ± 0.9 litres min −1 (% S a o 2 ) −1 . This was similar to the increase in hypoxic sensitivity which resulted from raising the end-tidal CO 2 by 0.5 kPa without adding doxapram. 4. The slope of the ventilatory response to rebreathing CO 2 rose from 11.6 ± 5.3 litres min −1 kPa −1 to 20,4 ± 9.8 litres min −1 kPa −1 during doxapram infusion. 5. The marked increase in the ventilatory response to CO 2 implies that doxapram has a central action, but the potentiation of the hypoxic drive also suggests that the drug acts on peripheral chemoreceptors, or upon their central connections, at therapeutic concentrations in normal unanaesthetized subjects.

1. The relationship between coughing and spinal monosynaptic reflexes (SMR) in extensors and flexors was investigated in eight healthy subjects by using the Hoffmann technique. Coughing exerted major depression (81% in extensor and 83% in flexor SMR). This depressant effect began simultaneously with the first cough and lasted through the coughing phase. Complete recovery to initial values occurred an average of 40 s thereafter. 2. in comparison, mental tasks induced only a slight decrease in SMR amplitude. in contrast, the Mueller and Valsalva manoeuvres induced facilitation. 3. During coughing, large variations in extensor amplitudes were observed that were coupled with the ventilatory cycle. Slight facilitation was observed during inspiration, but expiration induced pronounced depression, occurring 0.20 s after the beginning of the expiratory period. Experiments performed during baseline breathing failed to show any change throughout inspiratory or expiratory phases. 4. Chemical stimulation of irritant receptors (inhalation of citric acid) produced no specific modification of extensor responses compared with the effect of placebo inhalation (distilled water). 5. These data suggest that coughing exerts a major depressant effect on motor activity via a loop that possibly includes cardiopulmonary receptors and inhibitory supraspinal descending pathways.

1. Twenty patients with severe chronic airflow obstruction (CAFO), four of whom were hypercapnic, had greatly reduced ventilatory responses to rebreathing CO 2 under hyperoxic conditions, compared with the responses in normal subjects. 2. Mouth occlusion pressure ( P 0.1 ) responses to CO 2 were also reduced in the patients compared with those of normal subjects but the reduction was less severe than in the ventilatory response. 3. in ten patients with CAFO minimum pleural pressure during tidal breathing [ P pl min. (dynamic)] at a P co 2 of 8.0 kPa was only slightly less negative than in the normal subjects (−16.2 cm water vs −23.4 cm water). 4. During rebreathing end-expiratory volume (EEV) fell progressively in the normal subjects (mean fall = 800 ml); in the patients there was a progressive rise in EEV (mean rise = 390 ml). 5. When P pl min. (dynamic) was compared with minimum static pleural pressures at the same lung volume the patients were generating a much higher proportion of their available static pressure (47.0%) than the normal subjects (26.4%) at a P co 2 of 8.0 kPa, suggesting that despite the slightly less negative P pl min. (dynamic), inspiratory muscle activation was greater in the patients than in normal subjects. Similar conclusions were reached from an analysis of the inspiratory work of breathing. 6. We conclude that hyperinflation, by impairing the capacity of the inspiratory muscles to lower pleural pressure, reduces the ventilatory response to CO 2 and adds to the effects of abnormalities in pulmonary mechanics so that measurements of absolute pleural pressure or work of breathing underestimate inspiratory muscle activation in patients with severe CAFO. 7. Hyperinflation and severe airflow obstruction also reduce the change in P 0.1 for a given degree of inspiratory muscle activation. 8. Our results suggest that, despite the impaired pressure and ventilatory response to rebreathing CO 2 in the patients, their central respiratory drive was greater than that of the normal subjects.

1. Unexplained cardiorespiratory arrests have been reported in patients with diabetic autonomic neuropathy and these could be due to denervation of the carotid chemoreceptors. 2. We have studied the ventilatory response to transient hypoxia ( ) during exercise in 22 male diabetic patients, six with symptomatic and cardiovascular evidence to suggest diabetic autonomic neuropathy (DAN+) and 12 without these features (DAN−). 3. There was no difference in the ventilatory response to transient hypoxia between the different groups of diabetic patients ( in DAN+ patients = −0·9 ± 0·2 litre min −1 kPa −1 ; in DAN− patients = −1·2 ± 0·6 litres min −1 kPa −1 ) even allowing for differences in the level of exercise achieved (CO 2 production in DAN+ patients = 743 ± 103 ml/min; CO 2 production in DAN– patients = 800 ± 144 ml/min). These results fell within our normal range for ventilatory response to transient hypoxia at this level of exercise. 4. The heart rate response to transient hypoxia varied within the groups but was significantly ( P < 0·05) less in the patients with established diabetic autonomic neuropathy. 5. We conclude that the peripheral chemoreceptors are intact in diabetic autonomic neuropathy and that other mechanisms must be implicated in the unexpected cardiorespiratory arrests seen in these patients. 1. Unexplained cardiorespiratory arrests have been reported in patients with diabetic autonomic neuropathy and these could be due to denervation of the carotid chemoreceptors. 2. We have studied the ventilatory response to transient hypoxia ( ) during exercise in 22 male diabetic patients, six with symptomatic and cardiovascular evidence to suggest diabetic autonomic neuropathy (DAN+) and 12 without these features (DAN−). 3. There was no difference in the ventilatory response to transient hypoxia between the different groups of diabetic patients ( in DAN+ patients = −0·9 ± 0·2 litre min −1 kPa −1 ; in DAN− patients = −1·2 ± 0·6 litres min −1 kPa −1 ) even allowing for differences in the level of exercise achieved (CO 2 production in DAN+ patients = 743 ± 103 ml/min; CO 2 production in DAN– patients = 800 ± 144 ml/min). These results fell within our normal range for ventilatory response to transient hypoxia at this level of exercise. 4. The heart rate response to transient hypoxia varied within the groups but was significantly ( P < 0·05) less in the patients with established diabetic autonomic neuropathy. 5. We conclude that the peripheral chemoreceptors are intact in diabetic autonomic neuropathy and that other mechanisms must be implicated in the unexpected cardiorespiratory arrests seen in these patients. 1. Unexplained cardiorespiratory arrests have been reported in patients with diabetic autonomic neuropathy and these could be due to denervation of the carotid chemoreceptors. 2. We have studied the ventilatory response to transient hypoxia ( ) during exercise in 22 male diabetic patients, six with symptomatic and cardiovascular evidence to suggest diabetic autonomic neuropathy (DAN+) and 12 without these features (DAN−). 3. There was no difference in the ventilatory response to transient hypoxia between the different groups of diabetic patients ( in DAN+ patients = −0·9 ± 0·2 litre min −1 kPa −1 ; in DAN− patients = −1·2 ± 0·6 litres min −1 kPa −1 ) even allowing for differences in the level of exercise achieved (CO 2 production in DAN+ patients = 743 ± 103 ml/min; CO 2 production in DAN– patients = 800 ± 144 ml/min). These results fell within our normal range for ventilatory response to transient hypoxia at this level of exercise. 4. The heart rate response to transient hypoxia varied within the groups but was significantly ( P < 0·05) less in the patients with established diabetic autonomic neuropathy. 5. We conclude that the peripheral chemoreceptors are intact in diabetic autonomic neuropathy and that other mechanisms must be implicated in the unexpected cardiorespiratory arrests seen in these patients.

1. By using the rebreathing method, ventilatory responses to inhaled CO 2 were studied in patients with diabetic neuropathy. 2. Their general respiratory functions including vital capacity (VC) and forced expiratory volume in 1 s (FEV 1.0 ) were within normal ranges and ventilatory responses to CO 2 in the range 5.32-5.99 kPa were not significantly different between patients and normal subjects. However, ventilation in the patients was significantly less than that in normal subjects when the alveolar partial pressure of CO 2 ( P aco 2 ) was above 6.65 kPa. 3. The slope of the CO 2 response curves obtained during hyperoxic rebreathing was significantly less in the patients than in the normal subjects. In the patients CO 2 response curves with 15% (v/v) O 2 were either the same or had lower slopes than those measured with 100% O 2 . 4. The results suggest that both peripheral and central chemosensitivity, including the activity of the respiratory centre, are reduced in patients with diabetic neuropathy.

1. Methods were devised and evaluated for inducing breathlessness by submaximal graded exercise in healthy subjects while objective measurements of cardiorespiratory function were made. Breathlessness was assessed with serial visual analogue scales (VAS), but with various measures to enhance repeatability. 2. A high level of reproducibility was obtained in spite of the subjective nature of the assessment. Individual responses were described by the relationship between breathlessness and ventilation. The sensitivity of the method was demonstrated by the use of inspiratory resistances which disturbed this relationship and caused greater breathlessness for a given level of ventilation. 3. These methods were applied to six healthy subjects to analyse the effects of acute doses of diazepam and promethazine on breathlessness induced by graded exercise or by rebreathing carbon dioxide in a double-blind study. 4. During exercise, diazepam and promethazine did not reduce breathlessness, although there was a minor trend with promethazine. During exposure to elevated levels of carbon dioxide, diazepam and promethazine had no effect on breathlessness. Diazepam and promethazine produced similar levels of sedation, but neither drug had significant effects on the ventilatory response to carbon dioxide. These preliminary findings contrast with those reported for chronic diazepam in ‘pink puffers’. 5. Raised levels of carbon dioxide caused greater breathlessness in relation to ventilation than did exercise.

1. Continuous positive-pressure breathing (CPPB) at airway pressures of 0.65–1.00 kPa above ambient pressure has been used to produce a sustained inflation of the lungs of approximately 1 litre in six normal male subjects. 2. Lung inflation produced a reduction in the ventilatory response to carbon dioxide inhalation by slow rebreathing in oxygen over approximately 45 min, with a reduction in the slope of the V E / P et,CO 2 and V T / P et,CO 2 relations ( P et,CO 2 , = end-tidal P co 2 ). 3. The pattern of breathing is altered, so that for any given expired minute ventilation ( V E ), tidal volume ( V T ) is reduced with a fall in breath duration ( T t ) resulting from a decrease in inspiratory time ( T i ) with no change in expiratory time ( T e ). 4. The break point on the V T / T i relation is lowered.

1. In 18 patients with acute myocardial infarction, we measured ventilation, frequency, inspiratory duration and the pressure at the mouth 0.1 s after the onset of inspiration against an occluded airway; mean inspiratory flow and the fraction of the breathing cycle devoted to inspiration were calculated. Measurements were made on 2–3 consecutive days soon after admission and repeated 4–10 days after admission. 2. Eight patients showed no clinical evidence of left heart failure at any time; in these patients no changes in breathing pattern, ventilation or occlusion pressure were observed. 3. Ten patients were in heart failure, as judged by the presence of râles and/or hypoxaemia on day 1 of the study, and all had recovered on the last day. When in failure these patients demonstrated increased minute ventilation, occlusion pressure was increased more than was mean inspiratory flow and their breathing pattern was altered. Tidal volume was similar to that in patients without failure and did not change with time, but frequency was initially high and fell as recovery from failure occurred. The duration of inspiration was decreased during failure, so mean inspiratory flow was increased. The fraction of the breathing cycle devoted to inspiration was constant and similar to that in patients without failure. 4. While in failure no patients were acidotic and not all patients were hypoxaemic; administration of oxygen did not influence results in two patients during failure. 5. These results indicate that clinically detectable pulmonary oedema is associated with increased ventilatory drive, which cannot be explained on the basis of hypoxaemia or hypercapnia. The observed changes in breathing pattern were probably due at least in part to vagal reflexes, and these may have contributed to the increase in drive.

1. The ventilation and cardiac frequency during progressive exercise and the respiratory responses to breathing carbon dioxide have been measured in 33 female patients with mitral stenosis and in 31 control subjects. Compared with the control subjects, the patients' exercise ventilation and cardiac frequency were increased; the exercise tidal volume at standard minute volume, the vital capacity and the ventilatory response to carbon dioxide were reduced. The extent to which the standardized tidal volume was lower during exercise than during breathing carbon dioxide was correlated with the severity of the stenosis, as gauged by the increase in exercise cardiac frequency above the level predicted from anthropometric measurements. 2. Twenty patients were studied postoperatively. In the 12 who showed clinical improvement the exercise ventilation and cardiac frequency were reduced and the exercise tidal volume at a given minute ventilation was increased. The latter change occurred despite a reduction in vital capacity, which was probably a residual effect of thoractomy. There was no significant change in the response to breathing carbon dioxide. No material change in function was observed in the patients whose condition was not improved by the operation. 3. It is suggested that in mitral stenosis the tachypnoea which occurs during exercise, whilst mainly a mechanical consequence of the reduced vital, capacity, is also partly due to pulmonary congestion stimulating intrapulmonary receptors.

1. Oxygen breath tests were performed in seven patients with thyrotoxicosis. The inspired air was replaced by oxygen without their knowledge for 20 s and the fall in ventilation was recorded. 2. Ventilation fell significantly in all the patients within 40 s. The mean fall was 21·1% (se ± 1·7) below the control value. 3. β-Adrenoreceptor blockade with propranolol had little effect on this reduction in ventilation. The fall observed in five patients receiving propranolol was 19·6% (se ± 1·0). 4. After definitive treatment, which rendered the patients euthyroid, the observed reduction in ventilation after breathing oxygen was significantly less at 11·7% (se ± 1·2). 5. It is concluded that patients with thyrotoxicosis have an increased resting reflex hypoxic drive to respiration, when compared with the euthyroid state, and this is unaffected by β-adrenoreceptor blockade.

1. The effect of mental arithmetic tasks on ventilation, breathing pattern, oxygen intake and carbon dioxide output was studied during air breathing and carbon dioxide rebreathing in healthy subjects. 2. Ventilation and breathing frequency increased significantly on performance of the task during 4 min air breathing and 4 min rebreathing; tidal volume was unchanged. The slopes of the ventilatory, frequency and tidal volume responses to carbon dioxide changed little during task performance. 3. During 15 min air breathing, oxygen intake was unchanged with task performance. Carbon dioxide output increased significantly with task performance, as a result of wash-out of carbon dioxide from body stores by the increased ventilation. 4. Mental arithmetic had no effect on the coefficients of variation of the slope and position variables of the ventilatory, frequency and tidal volume responses to carbon dioxide. It is concluded that task performance does not improve the reproducibility of these responses.

1. The ventilatory response to severe metabolic acidosis was studied by measuring arterial blood carbon dioxide tension and pH in sixty-seven patients with blood pH < 7·10, none of whom had hypercapnia, pulmonary oedema, or chronic pulmonary insufficiency. The results were compared with those previously found in patients with uncomplicated diabetic ketoacidosis. 2. By that comparison, fifty-two of the sixty-seven patients with blood pH < 7·10 were judged to have ‘appropriate hypocapnia’, and fifteen had ‘submaximal hypocapnia’. Thirteen of the latter fifteen had circulatory failure and/or acute hypoxia, and seven of nine in whom it was measured had plasma lactate >9 mmol/l. 3. Hyperventilation was therefore usually well sustained in these patients with severe metabolic acidosis, except in most of those with acute tissue hypoxia. The latter may have had insufficient time to achieve maximum hyperventilation in response to their acidosis, or perhaps their submaximal hypercapnia presaged imminent failure of the hyperventilatory response.

1. Oxygen breath tests were performed in nine patients with diffuse pulmonary infiltration whose resting arterial P o 2 ( P a,o 2 ) ranged from 8·9 kPa to 11·8 kPa. The inspired air was suddenly replaced with oxygen for 30 s and the percentage fall in ventilation over the last 10 s was measured. 2. P a,o 2 rose rapidly and exceeded 16 kPa within 20 s in each patient. 3. The ventilation fell significantly in seven of the nine patients. It is concluded that these seven patients had a demonstrable reflex hypoxic respiratory drive at rest. This tended to be greatest in patients with the lowest P a,o 2 . The percentage falls in ventilation observed were similar to those previously reported at comparable P a,o 2 levels in patients with chronic bronchitis. 4. The resting arterial P co 2 ( P a,co 2 ) ranged from 50 to 5·8 kPa. It did not change by more than 0·3 kPa during the oxygen breath tests in any patient.

1. Maximal oxygen uptake (V̇o 2 max.), lung volumes, and ventilatory responses to carbon dioxide and hypoxia have been measured in identical twin athletes, who were trained to a similar high degree. 2. The results confirm previous findings for V̇o 2 max. and lung volumes in identical twins, and are in keeping with the suggestion that genetic factors play a major part in determining the ventilatory response to carbon dioxide and hypoxia.

1. Previous studies of the ventilatory response to metabolic acidosis have usually considered only patients with arterial blood pH above 7·10. To define the response during more severe acidaemia, arterial CO 2 tension and pH were measured in fifty-three episodes of diabetic ketoacidosis, including twenty-four with pH below 7·10, and ten with pH below 7·00. 2. The relation between arterial CO 2 tension, and both blood pH and plasma bicarbonate concentration, in these cases with generally severe metabolic acidaemia (mean pH 7·12 ± SD 0·13), was very similar to the relations between those variables found by others in patients with less severe acidaemia, such as that due to renal failure. 3. As arterial blood hydrogen ion activity increased, arterial CO 2 tension decreased inversely, reflecting well-sustained hyperventilation, even during profound acidaemia. 4. The inverse relation between arterial CO 2 tension and hydrogen ion activity suggests that during metabolic acidosis, alveolar ventilation increases in direct proportion to the increased blood hydrogen ion activity.

1. The extent of the reflex hypoxic respiratory drive was investigated in a group of patients who were hypoxaemic because of chronic bronchitis. 2. Oxygen was substituted for the inspired air for periods of 1–2 min. This produced a rise in arterial P o 2 ( P a,o 2 ) which varied considerably from patient to patient, but in each case the rate of rise was effectively linear with time. The resulting fall in ventilation, measured over 15 s periods, was compared with the P a,o 2 achieved. 3. In most patients the P a,o 2 did not reach hyperoxic levels. The total contribution of their peripheral chemoreceptor reflexes to their resting ventilation could not therefore be measured. The fraction of the ventilation abolished when the P a,o 2 was corrected to near-normal levels was measured instead. In two patients whose P a,o 2 on air was 6·0 and 6·5 kPa (45 and 49 torr) this fraction was 25 and 27%. In three patients whose initial P a,o 2 was 8·0–8·8 kPa (60–66 torr), it was 18–21%. In three patients with an initial P a,o 2 of more than 9·3 kPa (70 torr), it was 5–16%. 4. Each of these patients therefore had a reflex hypoxic respiratory drive. In the more severely hypoxaemic patients the fraction measured was an important part of the overall efferent drive to the respiratory muscles.

1. A progressive exercise test was performed on forty-four male and twenty-nine female healthy Europeans, aged between 20 and 64 years. Values for cardiac frequency (fH) and ventilation (V̇) were interpolated to standard (submaximal) oxygen uptakes (V̇o 2 ) of 0·751/min and 1·01/min. The tidal volume ( V t) at a ventilation of 20 and 301 BTPS/min was also determined ( V t 20 and V t 30 respectively). 2. The slope of the linear relationship between cardiac frequency or ventilation and oxygen uptake (SfH and SV̇ respectively) can be used as a measure of the fitness of an individual, as it indicates the increase in fH or V̇ that is obligatory for an increase in energy expenditure equivalent to an additional oxygen uptake of 1·0 1/min (about the increase necessary for walking on the level at a normal speed). By analogy with the responses of an athlete, a ‘fit’ subject is one in whom responses are economically low, i.e. SfH and SV̇ are lower than in sedentary individuals. Measures of SfH and SV̇ can also be used to indicate the demands of everyday activities on fH and V̇. 3. When SfH and SV̇ are related to the individual's capacity to adapt fH and V̇ from resting to predicted maximum values (‘adaptation capacity’ ACfH and ACV̇ respectively), the resulting index (SfH × 100/ACfH or SV̇ × 100/ACV̇) expresses the percentage of the adaptation capacity used for an additional energy expenditure equivalent to a V̇o 2 of 1·01/min, and can be considered a measure of the ‘physiological strain’ of exercise. The effects on exercise responses of differences in body muscle can be allowed for by multiplying this index by lean body mass (LBM). The lower the (size-adjusted) physiological strain index, the fitter the individual subject.

1. An analysis was made of the relationship which exists between arterial [H + ], P co 2 and [HCO 3 − ] in twenty-five patients with stable metabolic acidosis and alkalosis and in three normal subjects. 2. Contrary to previous reports, the relationship between P co 2 and [H + ] was nonlinear and could best be described in terms of a rectangular hyperbola ( P co 2 = 962/([H + ]-12). 3. The relationship between P co 2 and [HCO 3 − ] was curvilinear and best described by the quadratic function 23.8 ( P co 2 ) 2 −12 P co 2 [HCO 3 − ] −962 [HCO 3 − ] = 0. 4. The small acute changes in [H + ],−[HCO 3 − ] and P co 2 produced by infusion of the weak organic acid 5,5−dimethyl 2,4−oxazolidinedione (DMO) could be predicted from the curvilinear regression.

1. In contrast to the diminished ventilatory response to hypoxia which has been found at rest in cyanotic congenital heart disease, hyperventilation was noted on exercise in children who were cyanosed. 2. Sixteen children had low arterial oxygen saturations on exercise and thirteen of these hyperventilated by an amount similar to that reported in normal adults breathing hypoxic gas mixtures. 3. The three children who had little ventilatory response in relation to the increase of hypoxia during exercise all had a triad of long-standing cyanosis starting early in life, high haemoglobin concentration and low arterial oxygen saturation at rest in air.

1. Changes in ventilation during progressive exercise were measured in eleven normal subjects. Ventilatory response to carbon dioxide at rest was measured in the same subjects using a rebreathing method. 2. The range of ventilatory response to exercise was 16·6–32·0 litres min −1 (litres CO 2 min −1 ) −1 (mean 22·7; SD 5·35); response to O 2 uptake was 17·0–43·9 litres min −1 (litres O 2 min −1 ) −1 (mean 29·02; SD 9·07). Ventilatory response to CO 2 ( S co 2 ) ranged from 0·81 to 3·22 litre min −1 mmHg −1 (mean 1·87; SD 0·62). 3. There was a highly significant ( P < 0·001) correlation between the changes in response to increasing CO 2 output or O 2 uptake, and S co 2 . 4. The results are compatible with the suggestion that ventilation during exercise in normal subjects is directly related to their chemosensitivity to CO 2 , those having the highest sensitivity showing the greatest exercise ventilation.