A novel hypothesis to explain the bronchconstrictor effect of deep inspiration in asthma

BACKGROUND: In healthy subjects deep inspiration transiently dilates the airways, while many asthmatic subjects show bronchoconstriction by a mechanism which is incompletely understood. We hypothesised that the negative intrathoracic pressure associated with deep inspiration occurring in the context of increased leakiness of the airway vasculature may temporarily increase airway oedema and thus reduce luminal diameter in subjects with asthma. METHODS: The effects of non-forced deep inspiration and forced deep inspiration through resistance (generating enhanced negative intrathoracic pressure) on specific airway conductance (sGaw) were compared in 10 asthmatic and 11 healthy subjects. Each performed two respiratory manoeuvres: (1) sGaw was measured immediately after three deep inspirations without added resistance, each performed at a predetermined rate (equal to that when performed maximally through resistance); and (2) sGaw was measured immediately after three forced inspirations through resistance. RESULTS: Compared with deep inspiration without added resistance, sGaw was significantly reduced after deep inspiration through resistance in the asthmatic group by a mean (SD) of -13.5 (11.0)% (p=0.003) but was unchanged in the control group (-0.5 (12.4)%, p=0.67). CONCLUSIONS: Given the similar time-volume relationship in the two manoeuvres, the reduction in sGaw is unlikely to be due to differences in smooth muscle behaviour. It is suggested that the enhanced negative intrathoracic pressure acting across the airway capillaries increases airway wall oedema and reduces airway calibre. Such a mechanism operational during normal rapid deep inspiration might contribute to bronchoconstriction after deep inspiration in subjects with asthma.     

Effect of inhaled H1 and H2 receptor antagonist in normal and asthmatic subjects

The effects on airflow resistance of an inhaled H1 receptor antagonist, clemastine, and an H2 receptor antagonist, cimetidine, have been investigated in normal and asthmatic subjects. No significant changes in specific conductance (sGaw) were seen in six normal subjects. In eight asthmatic subjects a significant increase in forced expiratory volume in one second (FEV1) occurred at 60 min (< 0.02), and 120 (< 0.05) after the inhalation of clemastine, whereas inhaled cimetidine had no effect on airflow resistance. Clemastine and cimetidine were tested on histamine-induced bronchoconstriction in eight normal and eight asthmatic subjects. Clemastine significantly reduced the fall in sGaw in normal subjects and the fall in FEV1 in asthmatic subjects, whereas cimetidine had no protective effect. Clemastine and ipratropium bromide were tested on methacholine-induced bronchoconstriction in eight normal subjects. Ipratropium bromide, but not clemastine, significantly reduced the fall in sGaw after methacholine. These results suggest that in normal and asthmatic subjects histamine-induced bronchoconstriction is mediated predominantly via H1 rather than H2 receptors in the airways.     

Effect of prior bronchoconstriction on the airway response to histamine in normal subjects.

We have examined the effect of prior bronchoconstriction on the bronchial responsiveness to inhaled histamine in nine normal subjects. The airway response to increasing concentrations of histamine aerosol was assessed by measurement of specific airways conductance (sGaw) in a body plethysmograph. The threshold provocative dose of histamine needed to cause a 35% fall in starting sGaw (PD35) and the steepest slope of the response were measured from cumulative log dose response curves. Histamine challenges were performed in duplicate after premedication with 0.9% sodium chloride (control) or methacholine aerosol on separate days. The mean starting sGaw did not change significantly after inhalation of 0.9% sodium chloride but methacholine caused a mean reduction in sGaw of 42%. Mean control PD35 values did not differ significantly from mean PD35 values after methacholine. The mean steepest slope of the response after methacoline was 47% lower than the mean control value. There was a significant linear relationship between starting sGaw and the steepest slope for the control and for the methacholine premedicated challenges. The reduction in slope after methacholine was accounted for by the fall in starting sGaw. Because histamine PD35 was not altered by prior bronchoconstriction, it is concluded that the bronchial hyperresponsiveness of asthmatic subjects to non-specific bronchoconstrictor stimuli is unlikely to be a direct consequence of their low starting airway calibre.     

In vitro and in vivo effect of verapamil on human airway responsiveness to leukotriene D4.

The mechanism by which leukotriene D4 (LTD4) induces airway narrowing in man is unclear. We have investigated this by examining the effect of the calcium channel blocker verapamil on the sensitivity of in vitro preparations of human bronchi to LTD4 and methacholine, and on the bronchoconstriction induced in normal subjects by these agonists in vivo. In vitro smooth muscle sensitivity was assessed by the concentration of LTD4 and methacholine causing a 50% of maximum contraction (EC50) and as the maximum tension generated. Verapamil did not alter baseline tension or the response to LTD4 but did inhibit contractile responses to methacholine. In vivo studies were performed in six normal subjects; they inhaled increasing concentrations of LTD4 (0.4-50 micrograms/ml) or methacholine (2-64 mg/ml). Airway responsiveness in vivo was expressed as the provocation concentration (PC) of agonist producing a 35% fall in specific airways conductance (PC35sGaw) and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Verapamil did not alter baseline sGaw or V30(p). One subject did not respond to LTD4 on either day. In contrast to the in vitro results, verapamil produced a greater than 10 fold reduction in LTD4 induced bronchoconstriction, but had no effect on methacholine induced bronchoconstriction. These results suggest that in normal subjects bronchoconstriction induced by inhaled LTD4 is due to a combination of direct and indirect mechanisms.     

Beta-blockers in bronchial asthma: effect of propranolol and pindolol on large and small airways.

In 11 asthmatic subjects the relative magnitude and the site of airway bronchoconstriction were compared after the oral administration of 40 mg of propranolol and 2.5 mg of pindolol and the magnitude and site of bronchodilation produced by 0.5 mg subcutaneous terbutaline were tested after pretreatment with propranolol and pindolol. Specific airway conductance (sGaw) and peak expiratory flow rate (PEFR), both believed to reflect changes in large airways, and capacity isoflow (Ciso-v) and delta Vmax50, both believed to reflect changes in small airways, were determined before and after administration of placebo, pindolol, and propranolol. Treatments were given double blind and in random order. After the administration of propranolol we noted a significant bronchoconstrictive effect in the large airways (mean values of PEFR and sGaw, expressed as percentages of control values, decreased by 87.4% +/- 13.2% and 43.3% +/- 8.9%) and in the small airways (mean value of Ciso-v increased by 20.6% +/- 4.7% and that of delta Vmax50 decreased by 50% +/- 11.9% of control). By contrast, pindolol produced no significant effect on sGaw or PEFR but the tests of small airway function showed significant bronchoconstriction (mean values of Ciso-v increased by 12.9% +/- 2.6% and those of delta Vmax50 decreased by 47.2% +/- 9.2%). This action makes pindolol potentially dangerous in asthmatic patients. The bronchodilator action of terbutaline on large airways is diminished after the use of both propranolol and pindolol.     

Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic, and asthmatic subjects.

This study was designed to determine whether resistance to the airway effects of the beta-agonist, salbutamol, would develop in three groups of subjects while taking large doses of inhaled salbutamol. Six normal non-atopic, six atopic non-asthmatic, and eight atopic asthmatic subjects were studied by an identical technique. The development of resistance was assessed from salbutamol dose-response studies in which the airway response was measured as specific airway conductance (sGaw). Further evidence was sought in the atopic and asthmatic subjects by measuring the airway response to a standard histamine inhalation challenge and the protective effect of 100 micrograms salbutamol on this challenge, and by six-hourly peak flow recordings. Subjects were assessed before and during four weeks in which they took inhaled salbutamol regularly in doses increasing to 500 microgram quid in week 4. Normal subjects showed a progressive reduction in the bronchodilator (sGaw) response to salbutamol during the four weeks, indicating the progressive development of resistance. The atopic subjects, both asthmatic and non-asthmatic, showed no reduction in the response to salbutamol during the four weeks, nor any change in the response to histamine challenge or in regular peak flow readings. These results demonstrate that asthmatic patients do not develop bronchial beta-adrenoceptor resistance easily and suggests that they and atopic non-asthmatic subjects are less susceptible to its development than normal subjects.     

Comparison of the effects of inhaled ipratropium bromide and salbutamol on the bronchoconstrictor response to hypocapnic hyperventilation in normal subjects.

A double blind, placebo controlled comparison was made of the effects of nebulised ipratropium bromide (0.05 and 0.5 mg) and salbutamol (0.25 and 2.5 mg) on lung function and the airway response to hyperventilation in eight normal subjects. Both agents at both doses caused similar baseline bronchodilatation, confirming the presence of resting bronchomotor tone. The overall mean increases as percentages of control were 33% in specific airway conductance (sGaw), 10% in maximal flow after expiration of 50% of vital capacity, and 3.7% in FEV1. Hypocapnia (mean end tidal carbon dioxide tension 2.2 kPa) was produced by three minutes of voluntary hyperventilation and resulted in a mean fall in sGaw of 0.49 s-1 kPa-1 (20%). After inhalation of 0.25 mg salbutamol hypocapnic hyperventilation still produced a mean fall in sGaw of 0.55 s-1 kPa-1, whereas salbutamol 2.5 mg reduced this response to 0.15 s-1 kPa-1 (6%). After both doses of ipratropium the decrease in sGaw caused by hyperventilation was similar to the control. This suggests that bronchoconstriction in response to hypocapnic hyperventilation in normal subjects is not mediated via a cholinergic reflex.     

The nasal response to exercise and exercise induced bronchoconstriction in normal and asthmatic subjects.

Two studies were carried out to test the hypothesis that the fall and recovery of nasal resistance after exercise in asthmatic and non-asthmatic subjects are related to the development of bronchoconstriction after exercise. In study 1 nasal resistance (posterior rhinomanometry) and specific airway resistance (sRaw) were measured before challenge and one, five, 10 and 30 minutes after four minutes of exhausting legwork exercise in nine asthmatic subjects and nine age matched healthy subjects. One minute after exercise there was a reduction in nasal resistance of 49% (SD 15%) from baseline in the healthy subjects and of 66% (17%) in the asthmatic subjects. This response and the subsequent return of nasal resistance to baseline values did not differ significantly between the two groups despite a substantial difference in the change in sRaw, an increase of 74% (45%) in the asthmatic subjects 10 minutes after exercise, and no change in the non-asthmatic subjects. In study 2, nasal and specific airway resistances were monitored according to the same measurement protocol in six subjects with increased airway reactivity. Subjects exercised on two occasions, wearing a noseclip, once while breathing cold, dry air and once while breathing warm, humid air. The fall in nasal resistance was similar under both conditions (to 47% and 39% of baseline), through sRaw rose only after cold air inhalation (to 172% of baseline). The results indicate that the nasal response to exercise is not related to bronchial obstruction in asthmatic subjects after exercise or to the temperature or humidity of the air inspired through the mouth during exercise.     

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

BACKGROUND--Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. METHODS--Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. RESULTS--Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. CONCLUSIONS--MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation.     

Bronchodilatation induced by deep breaths in relation to transpulmonary pressure and lung volume.

Induced bronchoconstriction in normal subjects can be transiently reversed by a deep breath (airway hysteresis). The mechanisms of airway hysteresis are not fully understood. The aim of these studies was to determine whether the nature of the deep breath (slow or fast inspiration, five or 10 second breath hold) affects the resultant bronchodilatation. Bronchoconstriction was induced in 10 normal subjects by inhalation of histamine until specific airway conductance (sGaw) was halved (mean (SEM) post-histamine sGaw 0.099* (0.009) s-1 cm H2O-1). A subsequent deep breath to total lung capacity (TLC) increased sGaw by 57% (13%) and neither the rate of inspiration to TLC nor periods of breath holding at TLC produced a significantly different degree of bronchodilation. Reducing the volume of the deep breath produced progressively less bronchodilatation and this was no longer significant after a breath to 68% (2%) TLC. To determine whether the volume of the deep breath or the accompanying increase in transpulmonary pressure (PstL) was responsible for the effect on sGaw, subjects were studied with an oesophageal balloon in place with and without their chest strapped. Subjects took a deep breath to a PstL of 20 cm H2O after bronchoconstriction had been induced by histamine. The degree of bronchodilatation (mean (SEM) %) was not significantly different (strap on 25 (6), strap off 36 (5)) even though significantly larger lung volumes (as % TLC) were reached with the strap off (strap on 57 (2), strap off 78 (3)). These results suggest that PstL rather than lung volume during a deep breath determines airway hysteresis.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

Airway response to inhaled salbutamol in hyperthyroid and hypothyroid patients before and after treatment.

For many years the development of thyrotoxicosis has been known to cause a deterioration in asthma but the mechanism is unknown. We have studied the effect of thyroid function on airway beta adrenergic responsiveness in 10 hyperthyroid and six hypothyroid subjects before and after treatment of their thyroid disease. Airway adrenergic responsiveness was assessed by measuring specific airway conductance (sGaw) after increasing doses of inhaled salbutamol (10-410 micrograms). After treatment there was no difference in resting FEV1, sGaw, or thoracic gas volume. FVC increased in the hyperthyroid subjects but did not change in the hypothyroid subjects. In the hyperthyroid subjects there was a significant increase in delta sGaw after 35, 60, 110, and 41 micrograms salbutamol; in sGaw after 60, 110, and 410 micrograms salbutamol; and in the area under the salbutamol dose response curve (AUC) after treatment of the thyroid disorder. In the hypothyroid subjects there was a significant reduction in sGaw after 10 and 60 micrograms salbutamol and in the AUC after treatment. When all subjects were considered, there was a negative correlation between the AUC and serum thyroxine values. These findings suggest that an inverse relationship exists between the level of thyroid function and airway beta adrenergic responsiveness.     

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

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.     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.     

Mechanisms of neurokinin A- and substance P-induced contractions in rat detrusor smooth muscle in vitro

OBJECTIVE: To investigate the mechanisms of neurokinin A- and substance P-induced contractions of rat urinary bladder smooth muscle, and to compare them with those of the muscarinic agonist carbachol. MATERIALS AND METHODS: Rat urinary bladder strips were suspended under 1 g of tension in a physiological buffer at 37 degrees C, gassed with 95% O(2)/5% CO(2). Mechanical activity was recorded isometrically during exposure to neurokinin A and substance P. RESULTS: Both agents produced concentration-dependent contractions of smooth muscle strips which were unaffected by tetrodotoxin (1 micro mol/L), peptidase inhibitors (captopril, thiorphan and bestatin; 1 micro mol/L each) or piroxicam (10 micro mol/L). The rank order of potency of agonists was neurokinin A > substance P > carbachol. Contractile responses to neurokinin A and substance P, like the contractile responses to carbachol, were abolished in a nominally Ca(2+)-free medium and significantly reduced by nifedipine (1 micro mol/L). SKF-96365 (60 micro mol/L), an inhibitor of receptor-mediated Ca(2+) entry, abolished the nifedipine-resistant response to substance P and carbachol, and significantly attenuated the response to neurokinin A. Depleting intracellular Ca(2+) stores with thapsigargin (1 micro mol/L) significantly attenuated neurokinin A-induced contractions but had no effect on substance P- or carbachol- induced contractions. The Rho-kinase inhibitor, Y-27632 (10 micro mol/L), significantly reduced both phasic and tonic components of the contractile responses to neurokinin A, substance P and carbachol. CONCLUSION: The contractile responses induced by tachykinins in rat urinary bladder smooth muscle strips involve a direct action on smooth muscle and are not modulated by peptidases or prostanoids. Neurokinin A and substance P, like carbachol-induced contractions, depend on extracellular Ca(2+) influx largely through voltage-operated and partly through receptor-operated Ca(2+) channels. Intracellular Ca(2+) release contributes to the contractile response to neurokinin A but appears to have no involvement in substance P- and carbachol-induced contractions. Rho-kinase activation contributes to contractions induced by substance P, neurokinin A and carbachol.     

Effect of infused vasoactive intestinal peptide on airway function in normal subjects.

Vasoactive intestinal peptide, one of the putative neurotransmitters of non-adrenergic inhibitory nerves in human airways, is a potent relaxant of human airways in vitro. Previous in vivo studies of infused vasoactive intestinal peptide in asthmatic subjects have shown only a small bronchodilator effect, which may have been secondary to the cardiovascular effects of the peptide. The effect on airway function of infused vasoactive intestinal peptide was studied in normal subjects, who readily develop bronchodilation in response to a beta agonist. Separate experiments were designed to assess whether there is any synergy between this peptide and the beta agonist isoprenaline. Incremental doses of 1, 3, and 6 pmol/kg/min of vasoactive intestinal peptide were infused for 15 minutes. At 6 pmol/kg/min it caused a mean fall in systolic blood pressure from 108 to 88 mm Hg and a rise in heart rate from 71 to 95 beats/min. There was no significant change in specific airways conductance (sGaw) at any dose of vasoactive intestinal peptide. No significant changes were found with placebo. Isoprenaline (400 microgram) given by inhalation at the end of the infusion produced a mean increase in sGaw of 50%. Infused peptide caused no significant change in the cumulative dose-response curve for inhaled isoprenaline. The lack of effect of vasoactive intestinal peptide on airway responses in vivo may be due to rapid enzymatic breakdown of the peptide or to the fact that dosage has to be limited by the cardiovascular effects.     

Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux

BACKGROUND: Acid reflux may aggravate airway disease including asthma and chronic cough. One postulated mechanism concerns a vagally-mediated oesophageal-tracheobronchial reflex with airway sensory nerve activation and tachykinin release. AIM: To test the hypothesis that patients with airways disease and reflux have higher airway tachykinin levels than those without reflux. METHODS: Thirty-two patients with airways disease (16 with mild asthma and 16 non-asthmatic subjects with chronic cough) underwent 24 h oesophageal pH monitoring. Acid reflux was defined as increased total oesophageal acid exposure (% total time pH<4 of >4.9% at the distal probe). All subjects underwent sputum induction. Differential cell counts and concentrations of substance P (SP), neurokinin A (NKA), albumin and alpha2-macroglobulin were determined. RESULTS: SP and NKA levels were significantly higher in patients with reflux than in those without (SP: 1434 (680) pg/ml vs 906 (593) pg/ml, p=0.026; NKA: 81 (33) pg/ml vs 52 (36) pg/ml, p=0.03). Significantly higher tachykinin levels were also found in asthmatic patients with reflux than in asthmatic patients without reflux (SP: 1508 (781) pg/ml vs 737 (512) pg/ml, p=0.035; NKA: median (interquartile range 108 (85-120) pg/ml vs 75 (2-98) pg/ml, p=0.02). In patients with asthma there was a significant positive correlation between distal oesophageal acid exposure and SP levels (r=0.59, p=0.01) and NKA levels (r=0.56, p=0.02). Non-significant increases in SP and NKA were measured in patients with cough with reflux (SP: 1534.71 (711) pg/ml vs 1089 (606) pg/ml, p=0.20; NKA: 56 (43) pg/ml vs 49 (17) pg/ml, p=0.71). No significant difference in differential cell counts or any other biochemical parameter was noted between study groups. CONCLUSION: This study demonstrates increased airway tachykinin levels in patients with asthma and cough patients with coexistent acid reflux. This suggests airway sensory nerve activation in this population.     

Bronchodilator actions of xanthine derivatives administered by inhalation in asthma.

The airway response to the inhalation of four alkyl xanthines was studied in 17 subjects with moderately severe asthma (mean FEV1 1.19 litres, 42% predicted). Theophylline (10 mg/ml), glycine theophyllinate (50 mg/ml), theophylline ethylenediamine (aminophylline 50 mg/ml), and diprophylline (125 mg/ml) were administered by nebulisation and the airway response was measured as percentage change from baseline of specific airway conductance (sGaw). All xanthine derivatives had an unpleasant taste and produced coughing at the onset of nebulisation. All four xanthines produced a significant increase in sGaw by comparison with saline placebo, with a maximum mean increase from baseline of 35% for theophylline, 40% for glycine theophyllinate, 60% for aminophylline, and 32% for diprophylline. Inhalation of 200 micrograms salbutamol from a metered dose inhaler produced an additional increase in sGaw of 149%. Thus alkyl substituted xanthines administered by inhalation to patients with asthma cause significant short lived bronchodilatation, but this effect is small compared with that of a conventional dose of an inhaled beta 2 adrenoceptor agonist.     

Protective effect of drugs on bronchoconstriction induced by sulphur dioxide

The response to inhaled sulphur dioxide in eight normal, seven atopic, and 22 asthmatic subjects was studied by measuring thoracic gas volume and airway resistance in a whole-body plethysmograph. The fall in specific airway conductance in relation to the concentration of sulphur dioxide inhaled (0-20 ppm) was determined in all three groups. The specific airway conductance fell significantly in the atopic and asthmatic subjects but not in the normal group. In a double-blind study prior inhalation of disodium cromoglycate caused a significant reduction in the response to sulphur dioxide inhalation in atopic and asthmatic subjects. Prior treatment with inhaled ipratropium bromide blocked the response in the atopic subjects, but the effect was variable in the patients with asthma. Previous treatment with inhaled clemastine also reduced the response in patients with asthma, without causing a change in baseline specific conductance. We conclude that non-allergic bronchial hyperreactivity was increased in the atopic and the asthmatic subjects and that mediator release, in addition to a vagal reflex, has a role in such bronchoconstriction.     

Role of inflammation in nocturnal asthma.

BACKGROUND--Nocturnal airway narrowing is a common problem for patients with asthma but the role of inflammation in its pathogenesis is unclear. Overnight changes in airway inflammatory cell populations were studied in patients with nocturnal asthma and in control normal subjects. METHODS--Bronchoscopies were performed at 0400 hours and 1600 hours in eight healthy subjects and in 10 patients with nocturnal asthma (> 15% overnight fall in peak flow plus at least one awakening/week with asthma). The two bronchoscopies were separated by at least five days, and both the order of bronchoscopies and site of bronchoalveolar lavage (middle lobe or lingula with contralateral lower lobe bronchial biopsy) were randomised. RESULTS--In the normal subjects there was no difference in cell numbers and differential cell counts in bronchoalveolar lavage fluid between 0400 and 1600 hours, but in the nocturnal asthmatic subjects both eosinophil counts (median 0.11 x 10(5) cells/ml at 0400 hours, 0.05 x 10(5) cells/ml at 1600 hours) and lymphocyte numbers (0.06 x 10(5) cells/ml at 0400 hours, 0.03 x 10(5) cells/ml at 1600 hours) increased at 0400 hours, along with an increase in eosinophil cationic protein levels in bronchoalveolar lavage fluid (3.0 micrograms/ml at 0400 hours, 2.0 micrograms/l at 1600 hours). There were no changes in cell populations in the bronchial biopsies or in alveolar macrophage production of hydrogen peroxide, GM-CSF, or TNF alpha in either normal or asthmatic subjects at 0400 and 1600 hours. There was no correlation between changes in overnight airway function and changes in cell populations in the bronchoalveolar lavage fluid. CONCLUSIONS--This study confirms that there are increases in inflammatory cell populations in the airway fluid at night in asthmatic but not in normal subjects. The results have also shown a nocturnal increase in eosinophil cationic protein levels in bronchoalveolar lavage fluid, but these findings do not prove that these inflammatory changes cause nocturnal airway narrowing.