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Regular exposure to antimuscarinic drugs would be expected to upregulate airway muscarinic receptors and could cause a transient increase in airways obstruction if treatment was stopped or omitted. We have examined peak expiratory flow rate (PEFR) during treatment and forced expiratory flow in one second (FEV1) and airway responsiveness to three constrictor agonists (as the provocative dose of agonist causing a 20% fall in FEV1, (PD20)) following cessation of regular inhaled ipratropium bromide, in 13 subjects with mild stable asthma. Subjects inhaled placebo and ipratropium bromide, 80 microg q.i.d. for 14 days in a cross-over fashion with a 1 week run-in/wash-out period before and after each treatment period. Subjects recorded symptom scores and PEFR throughout the study, and FEV1 and PD20 to histamine, methacholine and metabisulphite were measured before and after cessation of treatment. When compared to baseline, FEV1 was lower after cessation of ipratropium than after placebo, with a significant difference 30 h after the last dose (difference 190 mL; 95% confidence interval (95% CI) 310-70 mL; p<0.02). FEV1 measured 6-10 days later, did not differ significantly. PEFR was significantly lower after cessation of ipratropium than after placebo on Day 15 (19-37 h after the last dose) (mean difference 4.6%; 95% CI 1.6-7.5%; p<0.01) but not on Day 16. There were no significant changes in PD20 histamine, methacholine and metabisulphite, symptom scores or rescue bronchodilator use after cessation of treatment. Thus, transient bronchoconstriction was found around 30 h after cessation of regular therapy with inhaled ipratropium for 2 weeks. The mechanism is unclear, as no evidence of muscarinic receptor upregulation was found. Although the changes were small and unlikely to be important for most patients, the results of this study indicate that the timing of lung function measurements relative to the last dose of ipratropium is important when interpreting the course of lung function in long-term studies.

Bronchial reactivity to agonists such as histamine is seen in both chronic bronchitis and asthma, two conditions with different pathological changes in the airways. Salbutamol, when given acutely, reduces bronchial reactivity in patients with asthma, but the mechanism has not been clarified. To determine whether the effect of salbutamol depends on the pathological changes underlying the increased reactivity, we have compared the effect of salbutamol and ipratropium on bronchial reactivity in nine patients with asthma and ten with chronic bronchitis. Each drug was given on separate days in increasing doses (5, 100, 750, 1,000 micrograms) according to a double-blind, randomized design. Changes in forced expiratory volume in one second (FEV1) and specific airways conductance (sGaw) were measured after each dose, and the provocative concentration of histamine causing a 20% fall in the FEV1 (PD20) was determined after the last dose. Salbutamol and ipratropium were equipotent in the asthmatic subjects and caused a similar maximal increase in FEV1 (0.58 and 0.57 l) and sGaw (0.166 and 0.154 s-1.kPa-1). The two drugs also produced similar changes in the patients with chronic bronchitis, although the maximum response to both drugs was smaller (FEV1 0.29 and 0.32 l; sGaw 0.056 and 0.060 s-1.kPa-1; p less than 0.05). Despite differences in bronchodilatation the increase in histamine PD20 following salbutamol was similar in the asthmatic and bronchitic subjects (2.26 and 1.90 doubling doses (DD)) and greater in both groups (p less than 0.05) than the change in PD20 with ipratropium (0.84 and 0.56 DD).(ABSTRACT TRUNCATED AT 250 WORDS)

The bronchial response to inhaled histamine has been suggested as an epidemiological tool for assessing the prevalence of asthma, though the exact relationship between reactivity and asthma is unknown. Tests of bronchial reactivity to histamine were carried out in 511 subjects aged 18-64 years, randomly selected from the population in two areas of the South of England, who had returned questionnaires on respiratory symptoms. Bronchial reactivity to less than or equal to 8 mumol histamine was present in 14% and was associated with positive skin test responses to common allergens and with smoking history. Both of these relationships were in turn dependent on age, skin sensitivity being the more important determinant of reactivity in the young and smoking the more important in older subjects. Bronchial reactivity was least prevalent in the 35-44 year age group. No independent effect on reactivity of sex, social class, or area of residence was detected, and no significant effect from recent respiratory tract infections. Interpretation of the bronchial response to histamine in selected groups of subjects must take account of age, atopic state, and smoking history.

The effect of suggestion on the airway response to 10 inhalations of normal saline followed by doubling concentrations of isoproterenol was assessed in 12 normal and 30 asthmatic subjects. It was suggested that the first 5 saline solutions contained a bronchoconstrictor and that the second 5 contained a bronchodilator, or vice versa, and that the first 4 isoproterenol solutions were inert, whereas the last was a bronchodilator. Nine asthmatic, but no normal subjects, bronchoconstricted after saline inhalation, with a mean fall in specific airway conductance (SGaw) of 40%. This was dose-dependent and was abolished when inhalations were carried out at 37 degrees C 100% relative humidity. Suggestion did not affect the airway response to saline or isoproterenol in either group, but it did influence the subjective impression of airway caliber recorded on a visual analogue scale. In this study, the bronchoconstriction after saline inhalation, previously attributed to the effect of suggestion, was caused by airway cooling.

1. We describe a method for assessing bronchial beta-adrenoceptor blockade quantitatively in man. Specific airway conductance is measured after increasing doses of inhaled salbutamol and the extent to which the dose-response curve is displaced to the right after beta-adrenoceptor blocking drugs is used to assess bronchial beta-adrenoceptor blockade. 2. Salbutamol dose-response curves were plotted for six normal subjects by measuring sGaw 15 min after increasing doses of inhaled salbutamol. Salbutamol produced a 30-70% increase in sGaw. 3. Salbutamol dose response curves were obtained 2 h after oral practolol (100 mg and 200 mg) and oral propranolol (40 mg and 80 mg) on separate days and were displaced to the right. 4. The mean dose ratios for practolol 100 mg and 200 mg were 1.2 and 2.1 and for propranolol 40 mg and 80 mg they were 21 and 61 respectively.

1. Airway, metabolic and cyclic nucleotide responses to intravenous salbutamol were measured in five patients with mild asthma who had taken no medication in the week before the study. The studies were repeated after the patient had taken regular inhaled salbutamol for 4 weeks, in doses increasing to 2000 micrograms daily in week 4. 2. The pretreatment airway, metabolic and cyclic nucleotide responses to salbutamol were similar to those previously reported in normal subjects. These patients therefore did not show evidence of partial beta-adrenoceptor blockade. 3. After 4 weeks' salbutamol therapy the airway response to intravenous salbutamol was unchanged. 4. The glucose, pyruvate and adenosine 3':5'-cyclic monophosphate (cyclic AMP) responses to intravenous salbutamol were depressed after regular salbutamol administration. The dose-response curve for non-esterified fatty acids and insulin, though displaced downwards, did not indicate an impaired response to salbutamol since the shape was unchanged. There was no significant change in the lactate, glycerol and total ketone response. 5. This study confirms that tissues differ in the ease with which they develop resistance to beta-adrenoceptor agonists. Asthmatic airways appear to be relatively protected from developing assistance when compared with other tissues in asthmatic patients and when compared with the airways of normal subjects.

1. The airway and metabolic responses to an intravenous beta 2-agonist salbutamol have been investigated in normal subjects before and after chronic administration of inhaled salbutamol, 1600 micrograms daily for 2 weeks. 2. Before chronic inhalation of salbutamol there was a dose-dependent increase in specific airway conductance after intravenous salbutamol in cumulative doses from 25 to 300 micrograms. 3. Measurement of concentrations of blood glucose, lactate, pyruvate, glycerol, ketone bodies, non-esterified fatty acids, insulin, plasma cyclic AMP and cyclic GMP were made after each increment of salbutamol and all showed an increase apart from cyclic GMP. 4. After chronic inhalation of salbutamol there was a decrease in the airway, metabolic and insulin response to intravenous salbutamol. The cyclic AMP response showed little change. 5. This study confirms the development of adrenergic resistance in the airways of normal subjects after large does of inhaled salbutamol and shows that this is associated with widespread metabolic adrenergic resistance.

The response to a beta2-agonist (salbutamol) was assessed by measuring specific airways conductance (sGaw) in healthy volunteers following increasing doses of inhaled or intravenous salbutamol. Regular inhaled salbutamol in doses exceeding 200 microgram four times a day produced a progressive loss of airways responsiveness to both inhaled and intravenous salbutamol (beta-agonist resistance). In salbutamol-resistant subjects full bronchodilator sensitivity was restored 3-5 h after intravenous hydrocortisone.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.

1 The airway response to inhaled prostaglandin E2 (PGE2) and the effect of oral propranolol on this response was studied in eight normal subjects in a double-blind randomised trial. The airway response was measured as specific airway conductance (sGaw). 2 Inhalation of PGE2 caused retrosternal soreness, coughing and an awareness of mucus production. Despite this, PGE2 caused bronchodilatation and reproducible dose-response curves were obtained, with a maximum increase in sGaw of 53%. 3 Inhalation of the diluent of PGE2, an ethanol/saline mixture, did not cause irritation nor did it alter sGaw. 4 Prior administration of propranolol 80 mg did not alter baseline sGAW, nor the response to PGE2, indicating that the action of PGE2 in vivo is unaffected by bronchial beta-adrenoceptor blockade. 5 This technique should be of value in studying bronchodilator prostaglandins and their interaction with other drugs.

Epidemiological problems arising from the absence of an agreed definition of asthma have led to the use of bronchial reactivity tests in community surveys of asthma prevalence. Since only a minority of the general population will develop bronchoconstriction in response to the dose of histamine considered acceptable for use in the community it is important to make maximum use of the data available. Several methods for summarising the information in the dose-response curve obtained from a histamine challenge test have been compared. A standardised histamine challenge test was administered to 797 subjects selected from two communities, and a repeat test to 106 subjects. The test was well accepted. For most subjects FEV1 rose initially after administration of histamine (median rise 100 ml), so maximum FEV1 was used as the baseline from which the 20% fall to achieve a PD20 was calculated. In order to use all the data rather than just two points on the FEV1-log dose graph, PD20 was estimated by means of curve fitting, and the values were compared with PD20 from linear interpolation. An exponential curve was found to fit the data well. Extrapolation from the maximum dose of 4 mumol up to 8 mumol was allowed in the estimation of PD20 by both methods. The curve fitting method gave slightly more reproducible PD20 values than did linear interpolation, and also gave more estimates in the range 0.03-8 mumol. The repeatability of PD20 compared well with that of asthmatic subjects tested in a clinical environment. Curve fitting has an advantage over linear interpolation in large community studies, for which analysis of data by computer is essential.