Exercise-induced airway obstruction in relation to chronic obstructive lung disease

Gimeno, F., Berg, W. Chr., Steenhuis, E. J., de Vries, K., Peset, R., and Sluiter, H. J. (1974).Thorax,29, 16-20. Exercise-induced airway obstruction in relation to chronic obstructive lung disease. Forty-two patients with chronic obstructive lung disease and clinically suspected exercise-induced airway obstruction were studied to ascertain whether those with proven exercise-induced airway obstruction had specific distinguishing features. Exercise-induced airway obstruction (defined as a fall of FEV₁ of at least 10% of the pre-exercise values) was detected in 20 of the 42 patients. These 20 were found to have a lower elastic recoil but were otherwise identical with the remainder as regards clinical and physiological abnormality. It is postulated that exercise-induced airway obstruction can be a manifestation of chronic obstructive lung disease.     

口服罗红霉素对慢性阻塞性肺疾病患者肺功能的影响

目的探讨口服罗红霉素对慢性阻塞性肺疾病（COPD）患者肺功能的影响,并分析其可能的机制。方法将50例COPD患者采用随机、单盲方法分成治疗组25例与对照组25例,其中对照组采用常规基础治疗,治疗组在常规基础治疗基础上口服罗红霉素0．15g,2次／d,并持续1年。观察两组患者治疗前后外周血中性粒细胞计数及肺功能的变化,统计分析两组患者发生病情急性加重及因此而需住院的次数。结果治疗组患者治疗前后外周血中性粒细胞计数差异有统计学意义（P〈0．05）;治疗组第1秒用力呼气容积占用力肺活量百分比（FEV1/FVC）、第1秒用力呼气容积占预计值百分比（FEV1％预计值）、最大通气量、清晨最大呼气流量治疗前后改变不明显（P〉0．05）,对照组却有明显下降（P〈0．05）,两组患者治疗前后肺功能的变化差异有统计学意义（P〈0.05）;治疗组急性加重10例次（40％）,对照组19例次（76％）;治疗组需住院6例次（24％）,对照组13例次（52％）,两组急性加重率及需住院率比较差异均有统计学意义（P〈0．05）。结论口服罗红霉素对COPD患者肺功能具有保护作用,其可能的机制与罗红霉素对中性粒细胞的抑制作用有关。     

The excessive use of inhaled corticosteroids in chronic obstructive pulmonary disease

Despite the fact that the recommendations of the main clinical guidelines have restricted the indications for inhaled corticosteroids in chronic obstructive pulmonary disease (COPD), currently more than 80% of patients are receiving this treatment in Spain, mostly with high doses. A detailed review of the literature does not justify the use of these high doses, a position that agrees with the recommendations of the FDA. A re-evaluation of their safety, the consistency of the data on their efficacy showing similar results with moderate doses and a better patient selection require the use of this treatment in COPD patients to be reconsidered.     

Levalbuterol in the treatment of patients with asthma and chronic obstructive lung disease

Effective asthma control requires long-term (anti-inflammatory) controller medications for patients with mild-persistent to severe-persistent disease, and quick-relief bronchodilator medication for all patients with asthma to control intermittent symptoms of cough, wheeze, and bronchoconstriction, as well as acute exacerbations. For patients with chronic obstructive pulmonary disease, quick-relief and long-acting bronchodilators are primarily used in the maintenance and treatment of associated symptoms, including shortness of breath. For many years, the most widely used bronchodilator has been racemic (R, S)-albuterol, a short-acting beta2-adrenergic agonist, commonly dispensed as an inhaled aerosol or solution. Until the introduction of levalbuterol inhalation solution (Xopenex) in 1999, all marketed forms of albuterol (including Ventolin and Proventil brands) were racemic mixtures composed of a 1:1 ratio of (R)- and (S)-stereoisomers. Administered as a proportionally equivalent nebulized dose, levalbuterol [(R)-albuterol] provides greater bronchodilation than racemic albuterol and, in the appropriate clinical setting, offers the possibility for improving clinical outcomes in patients with asthma and other obstructive airway diseases. Additionally, levalbuterol can be given at lower doses than racemic albuterol to provide comparable bronchodilation, with the potential for reduced beta-mediated adverse effects in adults and children. Only since the past decade has the technology to separate stereoisomers become available, and thus the biologic activities of the albuterol stereoisomers had not been established. Binding studies have demonstrated that (R)-albuterol binds to the beta2-adrenergic receptor with a high affinity, whereas (S)-albuterol binds with 100-fold less affinity than (R)-albuterol. Other evaluations have suggested that (R)-albuterol possesses the bronchodilatory, bronchoprotective, and ciliary-stimulatory properties of racemic albuterol, while (S)-albuterol does not contribute beneficially to the therapeutic effects of the racemate and was originally assumed to be inert. However, preclinical evaluations have shown that (S)-albuterol has effects that work in opposition to (R)-albuterol and may diminish the therapeutic effects of (R)-albuterol.     

Respiratory muscles in chronic obstructive pulmonary disease and asthma.

Chronic obstructive pulmonary disease (COPD) and asthma are characterized by airflow obstruction and significant increase of respiratory muscle workload, with concrete risk of ventilatory pump failure. Respiratory muscles, the main component of this pump, undergo structural and functional changes during the course of these diseases. Aim of the present paper is to analyze modifications of respiratory muscles in COPD and asthma. An analysis of the most important controlled clinical studies released during the past years was carried out. The patients suffered from chronic obstructive pulmonary disease and asthma. In COPD, respiratory muscles have to cope with an increased load, an intrinsic weakness and a mechanical disadvantage, especially in the diaphragmatic length-force relationship; in patients with acute asthma, the main features are a massive hyperinflation and a persistent inspiratory muscle activity during expiration. Modifications of respiratory muscles deserve great consideration not only for the complete comprehension of the underlying physiopathologic aspects of these diseases, but also for the optimal clinical management: a reduced pulmonary hyperinflation in COPD place the respiratory muscles in a better position of the force-length curve while great care must be payed to the metabolic and nutritional aspects. During asthmatic crisis respiratory muscles are subjected to a sort of intense training but anyway persistence of bronchospasm in most severe attacks can lead to exhaustion of the ventilatory pump and need of mechanical ventilatory support.     

Regular inhaled beta agonist in asthma: effects on exacerbations and lung function.

BACKGROUND: A comparison of the effects of regular upsilon as needed inhaled beta agonist treatment on the control of asthma in the last 16 weeks of each of two 24 week treatment periods has been reported. This paper presents additional information on exacerbations of asthma and trends in lung function, airways hyperresponsiveness to methacholine, and bronchodilator responsiveness during the entire 24 week periods of regular or as needed beta agonist treatment. METHODS: Subjects undertook a year long randomised, double blind crossover study of regular upsilon as needed inhaled beta agonist treatment. Fenoterol (400 micrograms) or matching placebo was inhaled as a dry powder four times daily for 24 weeks, then subjects crossed over to the alternative regimen. Treatment with inhaled corticosteroids was used by 50 of the 64 subjects in constant doses throughout the study. Symptoms, peak expiratory flow rates, and drug use were recorded daily, spirometry was performed every four weeks, and methacholine and bronchodilator responsiveness were measured every eight weeks. RESULTS: Exacerbations of asthma symptoms occurred earlier and more often during regular treatment with fenoterol and four of five severe exacerbations requiring admission to hospital occurred during the period of regular treatment. Prebronchodilator forced expiratory volume in one second (FEV1) was on average 0.15 litres lower (95% confidence interval (95% CI) 0.11-0.19) and vital capacity (VC) 0.12 litres lower (95% CI 0.08-0.16) than during the placebo period. Morning peak flow rates were significantly lower and evening peak flow rates significantly higher, with an increase in diurnal variation from 9.8% (95% CI 6.9-12.8) to 17.5% (95% CI 13.8-21.3) during regular treatment. Geometric mean concentration of methacholine causing a 20% fall in FEV1 from the value after saline (PC20) decreased significantly from 1.63 to 1.15 mg/ml, indicating increased bronchial hyperresponsiveness during regular treatment. Response to bronchodilator, as measured by the % increase in postbronchodilator FEV1 related to prebronchodilator FEV1, was maintained with no evidence for tachyphylaxis. CONCLUSION: Chronic use of inhaled fenoterol resulted in more exacerbations, a significant decline in baseline lung function, and an increase in airway responsiveness to methacholine in asthmatic subjects, but did not alter bronchodilator responsiveness. These findings support the previous report that regular inhaled beta agonist treatment is deleterious in the long term control of asthma.     

Role of airway receptors in the breathing pattern of patients with chronic obstructive lung disease.

To determine whether airway receptors are responsible for the rapid, shallow breathing pattern seen in hypercapnic chronic obstructive lung disease, 10 patients underwent upper airway anaesthesia with inhaled lignocaine in a placebo controlled study. There was a significant reduction in breathing frequency after lignocaine (p less than 0.001) that was due to an increase in expiratory time (p less than 0.001). The inspiratory time remained unchanged, but tidal volume increased significantly (p less than 0.02). It is concluded that, while airway receptors may have a role in determining the frequency of breathing in chronic obstructive lung disease, other factors are responsible for the reduced inspiratory time.     

Time-dependent effect of prostaglandin E2 inhalation on airway responses to bronchoconstrictor agents in normal subjects.

Studies were performed to investigate whether hyperresponsiveness of the airways could be induced in normal subjects by inhalation of prostaglandin E2 (PGE2). During the initial bronchodilator phase of PGE2 action the bronchoconstrictor effect of inhaled histamine was significantly antagonised. When bronchoconstrictor challenges were started shortly after the end of the bronchodilator response to PGE2, however, significant enhancement of the effects of both inhaled histamine and methacholine occurred. It was predominantly sensitivity to these agents that was increased, with a parallel shift of the dose-response curves towards increased bronchoconstriction. Thus PGE2 may be protective in the acute phase of a bronchoconstrictor challenge, but in a chronic inflammatory condition its net effect may be a balance between this beneficial action and a non-specific potentiation of the activity of bronchoconstrictor agents.     

Oral progesterone treatment in chronic obstructive lung disease: failure of voluntary hyperventilation to predict response.

Previous studies have shown that some patients with chronic obstructive lung disease and hypercapnia will respond to medroxyprogesterone with improvement in arterial blood gases. The exact mechanism of this effect is unclear but it is presumed to be a result of ventilatory stimulation. To determine whether the ability to correct arterial blood gas abnormalities by voluntary hyperventilation would predict a subsequent favourable response to progesterone, we studied 11 subjects with chronic obstructive lung disease and chronic hypercapnia. Five subjects had chronic obstructive lung disease of moderate severity with mean (SE) FEV1 1.8 (0.34) 1 maximum voluntary ventilation (MVV) 40.4 (7.16) 1/min-1, arterial oxygen tension (Pao2) 53.8 (2.40 mm Hg, and arterial carbon dioxide tension Paco2) 49.6 (3.91) mm Hg, and were able to normalise their blood gas tensions during voluntary hyperventilation (Pao2 85.4 (8.01) mm Hg; Paco2 32.8 (3.43) mm Hg). Six subjects had severe chronic obstructive lung disease with FEV1 0.77 (0.12) 1, MVV 19 (3.09) 1/min-1, Pao2 60.0 (2.89) mm Hg and Paco2 50.5 (1.38) mm Hg, and they could not significantly alter their blood gases with voluntary hyperventilation (Pao2 62.5 (3.19) mm Hg, Paco2 49.7 (1.84) mm Hg). The groups were similar in age, height, weight, and resting Pao2 and Paco2. Each subject received one month of oral placebo and one month of medroxyprogesterone acetate (Provera). 20 mg orally thrice daily, given in a randomised, double blind fashion. The groups responded similarly with a significantly higher Pao2 and lower Paco2 while having medroxyprogesterone acetate than while having placebo. Two patients with polycythaemia showed a reduction in haemoglobin concentration while taking progesterone. It is concluded that the response to medroxyprogesterone is not predictable from spirometric or blood gas changes after voluntary hyperventilation.     

肺保护性通气可减轻轻中度慢性阻塞性肺疾病老年患者围术期肺部感染

目的探讨肺保护性通气对全麻轻中度慢性阻塞性肺疾病(COPD)老年患者围术期肺部感染的影响。方法选择择期行全麻上腹部手术的轻中度COPD老年患者40例,男24例,女16例,年龄65~81岁,ASAⅠ~Ⅲ级,BMI 19~28kg/m~2,采用随机数字表分为肺保护性通气组(PV组)和常规通气组(CV组),每组20例。PV组行肺保护通气:IPPV,V_T 6ml/kg,PEEP 5~10cm H_2O,每隔30分钟进行手法肺复张;CV组行常规通气:IPPV,V_T 10 ml/kg,不使用PEEP及肺复张。于麻醉诱导前(T_1)、机械通气后2h(T_2)、术毕时(T_3)、术后6hT_4)和24h(T_5)采集静脉血检测IL-6和IL-8的浓度;记录麻醉前、术后第1、3、5、7天的临床肺部感染评分(CPIS)和术后肺部炎症发生情况。结果两组患者年龄、BMI、ASA分级、术中输液量、出血量、尿量、机械通气时间、手术方式、T_1~T_5时IL-6和IL-8浓度组间差异均无统计学意义。与T_1时比较,T_2~T_5时两组IL-6和IL-8浓度明显升高(P0.05)。与麻醉前比较,术后第1、3、5天CV组CPIS评分和术后肺部炎症发生率明显升高(P0.05);术后第1、3、5天PV组CPIS评分明显低于CV组(P0.05)。结论肺保护性通气不能降低开腹手术轻中度COPD老年患者围术期IL-6和IL-8浓度,但是可减少术后肺部炎症的发生,减轻术后5d内的肺部感染。     

Errors in the measurement of total lung capacity in chronic obstructive lung disease.

The standard plethysmographic method of measuring total lung capacity (TLC) has been reported to result in spuriously high estimates in patients with severe airway obstruction. The helium-dilution method is known to underestimate TLC in the same patients. To determine the magnitude of these possible errors we measured TLC by four methods in 20 patients with varying degrees of chronic obstructive lung disease and in 11 normal subjects. TLC was measured by (1) helium dilution (TLCHe); (2) a volume-displacement body plethysmograph, box volume being plotted against mouth pressure (TLCm); (3) the same body plethysmograph with volume plotted against pressure measured with an oesophageal balloon (TLCes); and (4) a radiological technique (TLCxr). In normal subjects there was no difference between TCLm (6.57 +/- 1.20) and TLCes (6.51 +/- 1.24). In the patients with chronic obstructive lung disease TLCm gave results significantly higher than those of any other method. If TLCes is taken as the closest estimate of true TLC, TLCm consistently overestimates and TLCHe underestimates TLC. There was no relationship between the degree of airway obstruction and (TLCm - TLCes) but there was between (TLCes - TLCHe) and severity of airway obstruction. We conclude that using mouth pressure in the plethysmographic measurement of TLC in patients with chronic obstructive lung disease results in consistent but slight overestimation of TLC.     

Vertebral compression fractures and mineral metabolism in chronic obstructive lung disease.

Chronic obstructive lung disease has been reported as a cause of osteoporosis, though whether this association is due to the disease itself or to corticosteroid treatment has not been elucidated. We studied 44 male patients with chronic obstructive lung disease (mean (SD) FEV1 39% (14%) of predicted normal) who were not having long term corticosteroids. No differences in a vertebral deformity score or in metacarpal index were found between them and a control group of similar age. Indices of bone formation (serum osteocalcin) and bone resorption (urinary hydroxyproline) were normal and parathyroid hormone and 1,25-dihydroxyvitamin D were also normal. Serum 25-hydroxyvitamin D was decreased, indicating depleted vitamin D. Calcitonin concentrations were higher in the patient than in the control group of the same age. There was no increase in the prevalence of osteoporosis in patients with chronic obstructive lung disease who had not received long term corticosteroid treatment. Increased concentrations of calcitonin may protect the skeleton from the detrimental effect of hypovitaminosis D.     

The effect of halothane, enflurane and isoflurane on resistance and compliance in patients with asthma or chronic obstructive lung diseases

In order to test the hypothesis that halothane is more effective and safer than enflurane and isoflurane in patients with reactive airway disease, a clinical trial was performed to compare these three agents in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS. After obtaining institutional approval and informed consent, 31 patients with bronchial asthma or COPD were studied (FEV1 less than 65% of FVC); all patients underwent extensive surgery of the paranasal sinuses. Premedication consisted of i.m. atropine and promethazine; anesthesia was induced with diazepam, fentanyl, etomidate, and succinylcholine and maintained with pancuronium and 50% N2O in O2 together with one of the volatile agents, halothane, enflurane, or isoflurane, selected at random. Patients were mechanically ventilated. On the basis of respiratory pressures, volumes, and flows, inspiratory (Rin) and expiratory (Rex) resistance and compliance (C) were calculated after induction (control), 15 min after the addition of the volatile agent (1.25 MAC), every 15 min during the surgical procedure, and at the end of the operation. RESULTS. In 1 case, airway resistance increased markedly a few minutes after administration of isoflurane. The results obtained in this patient were not included in the evaluation of the data. There were no statistically significant differences in the preoperative data or control values of Rin, Rex, and C among the three groups (n = 10 each). With the respective inhalational agents, Rin increased maximally between 3% (halothane) or 8% (enflurane) and 21% (isoflurane), Rex between 16% (halothane, enflurane) and 29% (isoflurane). For the most part, however, these changes were not statistically significant as compared with controls. Intergroup comparisons failed to reveal any statistically significant differences either. In all groups C decreased continuously to about 90% of control. DISCUSSION. The results show that in patients with asthma or COPD, airway resistance remains virtually unchanged during surgery and anesthesia under halothane or enflurane anesthesia. With isoflurane, however, the resistance may rise by a slight but not statistically significant extent. Furthermore, marked bronchospastic reactions occurred in 2 patients in the isoflurane group. Thus, the three volatile anesthetics studied were not found to be unequivocally safe and effective in preventing increases in bronchomotor tone. However, pharmacodynamic effects other than those on respiration (e.g., cardiovascular actions, arrhythmogenic threshold, metabolism, toxicity) must additionally be taken into consideration.     

Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5'-monophosphate in non-atopic asthma.

Inhaled adenosine 5'-monophosphate (AMP) causes bronchoconstriction in atopic asthma, probably after in vivo conversion to adenosine. It has been suggested that adenosine potentiates preformed mediator release from mast cells on the mucosal surface of the airways by interacting with specific purinoceptors, without affecting the release of newly generated mediators. The airway response of nine non-atopic subjects with "intrinsic" asthma to inhaled AMP and the influence of the oral, selective H1 histamine receptor antagonist terfenadine on this response was investigated. The geometric mean provocation concentrations of histamine and AMP required to produce a 20% fall in FEV1 (PC20) were 1.82 and 13 mmol/l. In subsequent placebo controlled time course studies the FEV1 response to a single inhalation of the PC20 histamine was ablated after pretreatment with oral terfenadine 180 mg. This dose of terfenadine caused an 80% inhibition of the bronchoconstrictor response to the PC20 AMP when measured as the area under the time course-response curve and compared with the response to PC20 AMP preceded by placebo. Terfenadine 600 mg failed to increase protection against AMP further, but both doses of terfenadine delayed the time at which the mean maximum fall in FEV1 after AMP was achieved. Terfenadine 180 mg had no effect on methacholine induced bronchoconstriction in the same subjects. These data suggest that inhaled AMP may potentiate the release of preformed mediators from preactivated mast cells in the bronchial mucosa of patients with intrinsic asthma.     

Morphometry of pulmonary arteries from angiograms in chronic obstructive lung disease.

The application of morphometric techniques based on Strahler orders to the study of pulmonary angiograms is described. When the pulmonary arterial tree is ordered by Strahler's method, peripheral branches have the lowest orders and the main pulmonary artery the highest order. The mean diameter of vessels in each order can then be determined. Pulmonary angiograms were obtained from 16 patients, 10 of whom had chronic obstructive lung disease (COLD), the other six having normal angiograms. Six orders of branching were found in vessels of 1 mm diameter or greater, and a plot of log mean diameter versus order from the normal angiograms was linear. The mean diameters of orders 2, 3, and 4 (diameter 2 to 7 mm) from COLD patients were significantly reduced ((p less than 0.01) and the log mean diameter versus order plot was concave upwards. These changes were more marked when TLC was raised than when it was normal. Plots of diameters of vessels from zones of the lung in which the pathology was well advanced (as judged by radiological changes) showed even greater reduction in the middle orders. These changes are probably the result of stretching of vessels in emphysematous lesions and diminution of blood flow from loss of capillary bed.     

Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.     

Assessment of reversibility of airway obstruction in patients with chronic obstructive airways disease.

Spirometry before and after an inhaled beta agonist or a course of oral prednisolone is widely used to detect reversible airflow limitation in patients with chronic obstructive lung disease. How many of these patients have a response and how the response to beta agonists relates to the response to corticosteroids is not clear. In 127 outpatients (mean (SD) FEV1 0.92 (0.38) 1) who had a clinical diagnosis of chronic obstructive lung disease (continuous breathlessness for more than six months and an FEV1/forced vital capacity (FVC) ratio less than 60%) and who appeared to be stable, the change in FEV1 was measured after salbutamol 200 micrograms from a metered dose inhaler and 5 mg from a nebuliser. Symptoms and spirometric values were recorded before and after two weeks of oral prednisolone 30 mg. Reversibility was defined as a response in FEV1 of 15% or more from baseline alone and as a 15% change and a minimum increase of at least 200 ml. The latter gave results that showed greater internal consistency between the drug regimens. On the basis of this criterion 56 patients (44%) had no response to salbutamol or prednisolone, 71 responded to salbutamol (including all 27 steroid responders), and 25 patients had a response to salbutamol 5 mg but not to 200 micrograms. In general, the largest increase in FEV1 after salbutamol occurred in the subjects with greatest improvement after prednisolone. Subjects showing a response in FEV1 after two weeks' prednisolone had a fall in total symptom score, unlike those who had no response to any treatment or a response to salbutamol only. These data show that reversibility in response to beta agonists is common in patients diagnosed on clinical grounds as having stable chronic obstructive lung disease, that it can be substantial, and that it is best detected by using a larger dose of salbutamol. Salbutamol responders were those most likely to improve after a trial of oral prednisolone. Allowance should be made for the variability of FEV1 in the calculation of the percentage response at low baseline values (less than 1 litre).     

Interactions between response to inhaled prostaglandin E2 and chronic beta-adrenergic agonist treatment.

Cumulative inhalation dose-response curves for the response to prostaglandin E2 (PGE2) have been constructed in normal subjects and patients with mild, stable asthma. In normal subjects cumulative inhalation dose-response curves were also constructed for salbutamol. In normal subjects dose-related bronchodilatation occurred in response to both PGE2 and salbutamol, although both the within-subject and the between-subject variation was significantly greater with salbutamol. Most asthmatic subjects gave a biphasic response to PGE2 on at least one occasion, PGE2 being a bronchoconstrictor above a certain level of specific airways conductance (sGaw) and a bronchodilator below. Chronic treatment with inhaled salbutamol (400 micrograms four times a day) had no effect on the normal subjects' response to salbutamol but there was a significant shift of the PGE2 dose-response curve to the left, indicating increased bronchodilatation (p less than 0.02). Stabilisation of the asthmatics' dose-response curve in the direction of bronchodilatation also occurred and was more pronounced (p less than 0.005). In the normal subjects PGE2 may be concerned in the control of airway smooth-muscle tone and in limiting bronchoconstriction induced by mediators such as histamine, and chronic salbutamol treatment may be important in enhancing these effects of PGE2. 80 mg oral propranolol given one and a half hours before had no effect on PGE2-induced bronchodilatation; but the question whether chronic treatment with beta-blockers has any effect needs investigation.