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Modulation of substance P-induced bronchoconstriction by lipoxygenase metabolites.

In anaesthetized, mechanically ventilated guinea-pigs, substance P induces a bronchoconstrictor response comprising increases in airway resistance and decreases in dynamic compliance. Eicosatetraynoic acid (ETYA, 20 mg kg-1 i.v.) or BW755c (20 mg kg-1 i.v.) potentiated the substance P-induced bronchoconstriction. Neither indomethacin (1 or 5 mg kg-1 i.v.) nor aspirin (20 mg kg-1 i.v.) significantly altered the potency of substance P on bronchomotor responses. These observations are consistent with the existence of a bronchodilator lipoxygenase metabolite(s).

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

The effect of TYB-2285 on dual phase bronchoconstriction and airway hypersensitivity in guinea-pigs actively sensitized with ovalbumin.

The effect of a new anti-asthmatic drug, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), was investigated in ovalbumin-sensitized guinea-pigs. When guinea-pigs were pretreated with TYB-2285 (300 mg kg-1, p.o., single dose or consecutively for 7 days), the immediate asthmatic response was inhibited as demonstrated by diminished cyanosis, but not the bronchoconstriction. TYB-2285, given singly or consecutively, inhibited the appearance of late asthmatic response and the infiltration of inflammatory cells, such as eosinophils, into the airway. Additionally, airway hyper-responsiveness was also reversed by the single administration of TYB-2285. Luminol-dependent chemiluminescence of airway-infiltrated cells stimulated with A23187 was inhibited by TYB-2285 in a dose-dependent manner. The present study suggests that TYB-2285 inhibits late asthmatic response and airway hyperresponsiveness by inhibiting the accumulation of eosinophils and other inflammatory cells into the airway, and also by inhibiting the production of oxygen radicals from airway-infiltrated cells.

Animals↗

Cotton induced bronchoconstriction detected by a forced random noise oscillator.

Lung function responses to inhaled cotton dust were evaluated in a group of 58 healthy subjects by spirometry (MEFV curves) and forced random noise impedance parameters. Twenty-one of these subjects were also examined by body plethysmography to assess changes in airway resistance (Raw). For the study group as a whole, alterations in lung mechanical function after exposure to cotton dust were detected by maximal expiratory volumes and flows (p less than 0.001) and impedance parameters (p less than 0.01) but not by Raw. Subjects showing responses in MEFV curves also showed increases in Thevenin or effective resistance at low frequencies (R1, R5-9, R5-9/R20-24), suggesting that the limitation of flow occurred predominantly in the peripheral airways. By contrast, non-responders on MEFV measurements were found to have significant increases in effective resistance both at low and at high frequencies (R1, R5-9, R20-24), suggesting a central airways effect. MEFV curve non-responders also exhibited a significantly lower baseline effective resistance profile than MEFV curve responders. The data indicate that under the conditions of the experiment measures of the Thevenin resistance (real part of impedence) by the forced random noise method are reliable indicators of cotton induced bronchoconstriction. Measurement variability, however, suggests that, at present, these are more appropriate for group studies and should remain adjuncts to standard tests of lung function such as spirometry.

Adult↗

Inhaled antihistamines--bronchodilatation and effects on histamine- and methacholine-induced bronchoconstriction.

To assess further the bronchodilator activity of inhaled antihistamines ten stable asthmatic subjects inhaled aerosols of clemastine, 1 mg/ml, and saline placebo administered double blind. Subjects underwent bronchial challenge with increasing concentrations of histamine and methacholine, and specific airways conductance was measured by whole body plethysmography at each concentration. There was a significant 21.9% increase in specific airways conductance after inhalation of clemastine. Subjects could tolerate significantly higher mean concentrations of histamine when treated with clemastine than with saline. The shift of the cumulative log histamine dose-reponse curve suggests that such protection is due to competitive antagonism to the inhaled clemastine. Clemastine did not protect subjects against methacholine-induced bronchoconstriction, which suggests that its bronchodilator properties are not related to any anticholinergic action.

Adult↗

Plasma catecholamines during exercise-induced bronchoconstriction in bronchial asthma.

Plasma levels of adrenaline and noradrenaline during and after submaximal exercise in patients with bronchial asthma were investigated. Three groups were studied comprising 10 patients with exercise-induced bronchoconstriction (EIB), 10 asthmatic patients without EIB and four normal control subjects. Plasma catecholamines were measured at rest, at the end of exercise, and five and 15 minutes after exercise. Changes in airway resistance were assessed by measuring peak expiratory flow rate. Significant differences in catecholamine levels between reacting and non-reacting patients were found. In 10 patients developing EIB adrenaline and noradrenaline levels had risen significantly by the end of exercise and remained elevated up to the fifth minute of recovery. The rise in catecholamine levels in non-reacting asthmatics was insignificant. In control subjects noradrenaline had increased significantly by the end of exercise.

Adult↗

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.

Adolescent↗

Inhibition by sodium cromoglycate of bronchoconstriction stimulated by respiratory heat loss: comparison of pressurised aerosol and powder.

The protective effect was examined of three doses (2, 10, and 20 mg) of sodium cromoglycate inhaled from a pressurised metered dose inhaler on the response to isocapnic hyperventilation of cold dry air in 10 asthmatic subjects. This was compared with the effect of cromoglycate powder (20 mg) inhaled from a Spincap and with placebo given on two occasions. The medications were inhaled on separate days, in random order and with the use of a double blind double dummy technique, 20 minutes before isocapnic hyperventilation of two fold increasing volumes of air (-15 degrees C, 0% humidity) to produce a 20% fall in the post-treatment FEV1. The response was expressed as the provocative dose of respiratory heat loss required to cause a fall in FEV1 of 15% (PD15, kcal/min). The mean baseline spirometric indices exceeded 85% of predicted normal values on each test day; both placebo treatments reduced the baseline FEV1 by comparison with all active treatments (p less than 0.0001). Comparison of the PD15 on the two placebo days confirmed excellent reproducibility. All doses of cromoglycate shifted the respiratory heat loss dose-response curve to the right of the placebo curve; PD15 after all active treatments exceeded PD15 after placebo (p less than 0.0001). There was no cromoglycate dose-response relationship between the three doses of aerosol (p greater than 0.05), or between any dose of aerosol and powder (p greater than 0.05). It is concluded that cromoglycate aerosol inhaled from a pressurised inhaler in a dose of 2 mg gives the same magnitude of protection against bronchoconstriction stimulated by airway cooling as 20 mg of pressurised aerosol or powder from a Spincap.

Adult↗

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.

Adult↗

Abolition of methacholine induced bronchoconstriction by the hyperventilation of exercise or volition.

Total pulmonary resistance was measured from continuous records of flow and oesophageal pressure in five normal subjects on three separate days before and after inhalation of methacholine. The dose of methacholine produced, on average, a fivefold increase in airway resistance. Immediately after methacholine inhalation the subjects underwent a progressive exercise test on a cycle ergometer (day 1) or voluntary hyperventilation (day 2) or remained resting (day 3). On the first day during exercise pulmonary resistance fell rapidly to baseline levels within two to three minutes and remained there for the 10 minute duration of the exercise. On day 2 voluntary reproduction of the same level and pattern of ventilation as during exercise resulted in a similar fall of resistance. On the third day, when the subjects remained at rest, pulmonary resistance remained raised for 10 minutes. It is concluded that the bronchodilator effects of exercise can be explained by the increased ventilation rather than the exercise itself, but with much smaller tidal volumes than have previously been thought necessary to reduce drug induced bronchoconstriction.

Adult↗

Refractory period following bronchoconstriction provoked by histamine in asthmatic subjects.

To determine whether refractoriness to histamine induced bronchoconstriction occurs, 20 asthmatic subjects aged 19-50 years were tested. Subjects underwent two histamine challenge tests (1 and 2) on the same day, the second one being given 45-60 minutes after the first, once the FEV1 after test 1 had returned spontaneously to within 90% of baseline. A further "control" histamine challenge test was carried out on a different day at the same time (+/- 2 hours) as test 1. Bronchial responsiveness was recorded as the cumulative dose (microgram) of histamine provoking a 20% fall in FEV1 (PD20), and the ratio PD20 test 2:PD20 test 1 was used to assess refractoriness. The median value of this ratio (2.20) was significantly greater than 1 (p = 0.003), indicating refractoriness at the time of test 2. By contrast the median ratio PD20 control:PD20 test 1 of 1.03 was not significantly different from 1. Refractoriness could not be accounted for by failure to regain the initial baseline FEV1, though such failure may have exaggerated the effect. An increase in PD20 with the second test was observed uniformly in subjects with moderate or high initial PD20 values but not in those with low values. This suggests that there may be a PD20 threshold of the order 25-100 micrograms for refractoriness to occur. Refractoriness could exert an important confounding effect in investigations in which repeated histamine tests are carried out at short intervals.

Adult↗

Inhibition of sodium metabisulphite induced bronchoconstriction by frusemide in asthma: role of cyclooxygenase products.

BACKGROUND: Inhaled frusemide inhibits airway responses to sodium metabisulphite and other indirect bronchial challenges in asthma by undetermined mechanisms which may relate to its ability to stimulate prostaglandin release. Inhalation of sodium metabisulphite provokes indirect bronchoconstriction, possibly by activating sensory nerves. To investigate the role of cyclooxygenase products in the airway actions of frusemide and sodium metabisulphite, the effects of a potent cyclooxygenase inhibitor, flurbiprofen, alone and in combination with frusemide were investigated against airway responsiveness to sodium metabisulphite. METHODS: In a double blind double placebo controlled study, 12 mild asthmatic subjects attended on four occasions to undergo three inhalation challenges with sodium metabisulphite. A baseline challenge was performed one hour before oral intake of flurbiprofen 200 mg or matched placebo, and two hours before inhalation of frusemide 40 mg or matched placebo. A second challenge was performed immediately after inhalation of frusemide (two hours after flurbiprofen) with a further challenge three hours later. The log concentration provoking a 20% fall in FEV1 (log PC20) was used to assess airway responsiveness to sodium metabisulphite. RESULTS: Frusemide caused an immediate 1.9 doubling dose protection and a lesser 0.7 doubling dose protection at three hours. This protection was enhanced by flurbiprofen at both time points to 2.7 (early) and 1.9 (late) doubling doses. In addition, flurbiprofen alone significantly reduced airway responsiveness to sodium metabisulphite by 1.1 doubling doses at both two and five hours. CONCLUSIONS: The generation of bronchoprotective prostaglandins is unlikely to underlie the inhibitory action of frusemide against airway responsiveness to sodium metabisulphite. Endogenous contractile prostaglandins within the airways may be involved in the bronchoconstrictor response to sodium metabisulphite.

Adult↗

Effect of acute alterations in inspired oxygen tension on methacholine induced bronchoconstriction in patients with asthma.

BACKGROUND: Recent in vitro and in vivo studies in animals have suggested that ambient oxygen tension may influence airway responsiveness to bronchoconstrictor stimuli. These observations may have relevance to the management of acute exacerbations of asthma. The present studies were designed to examine the influence of inspired oxygen tension (Fio2 1.0, 0.21, 0.15) on methacholine-induced broncho-constriction in patients with asthma. METHODS: In a dual study two groups of asthmatic patients performed methacholine inhalation challenges breathing either air (Fio2 0.21) or a hypoxic gas mixture (Fio2 0.15) in study 1 and air (Fio2 0.21) or hyperoxia (Fio2 1.0) in study 2. The gases were administered through a closed breathing circuit in a randomised double blind fashion. The PC20 values (dose of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) were calculated after each methacholine challenge by linear interpolation from the logarithmic dose response curve. Plasma catecholamine levels were measured before and after methacholine challenges as well as heart rate, oxygen saturation, and percentage end tidal carbon dioxide levels. RESULTS: The geometric mean PC20 value for methacholine was significantly lower on the hypoxic study day than on the normoxic day in study 1 (mean difference in PC20 values 2.88 mg/ml (95% CI 1.4 to 5.3); p < 0.05), but there was no significant difference in the geometric mean PC20 value for methacholine between the hyperoxic and normoxic study days in study 2 (mean difference in PC20 values 1.45 mg/ ml (95% CI 0.83 to 2.51)). CONCLUSIONS: Acute hypoxia potentiates methacholine induced bronchoconstriction and acute hyperoxia has no effect in mild to moderate patients with stable asthma.

Administration, Inhalation↗

Effects of timolol, indomethacin, and MK-571 on bronchoconstriction to infused leukotriene D4 in guinea pigs.

Continuous intravenous infusions of leukotriene D4 produced a prolonged but variable bronchoconstriction (approximately a 200% increase in lung resistance (RL) and a 50% decrease in dynamic compliance (Cdyn] in anesthetized and paralysed guinea pigs that peaked within 1-1.5 min and was followed by a somewhat smaller secondary plateau response. The overall response was delayed (time to peaks) but not significantly reduced by pretreatment with the cyclooxygenase inhibitor indomethacin (1 mg/kg), was markedly potentiated by the beta-adrenoceptor antagonist timolol (5 micrograms/kg), and was partially and completely blocked by pretreatment with 0.1 and 1.0 mg/kg, respectively, of the leukotriene D4 receptor antagonist MK-571. MK-571 prevented the response in indomethacin-treated guinea pigs but was considerably more active at preventing and reversing the potentiated responses (lower dose of leukotriene D4) in animals treated with indomethacin and timolol. Additional studies in indomethacin- and timolol-treated animals demonstrated that MK-571 was active with good duration of action by the aerosol route of administration (30 min and 4 h pretreatment). The technique of infusing leukotrienes into untreated, indomethacin-treated, and indomethacin- and timolol-treated guinea pigs is a useful method to study the action and interaction of leukotriene receptor antagonists.

Aerosols↗

Reflex bronchoconstriction induced by capsaicin in the dog.

To determine whether receptors stimulated by the injection of capsaicin into the pulmonary circulation cause reflex changes in airway size, six dogs were anesthetized with chloralose, paralyzed with succinylcholine, and mechanically ventilated (2 cm H2O PEEP). Intrapulmonary airways were outlined with tantalum dust, and diameters were determined by taking serial roentgenograms at end expiration. Capsaicin (20 micrograms/kg) injected into the right ventricle significantly decreased airway diameter (20%), heart rate, aortic pressure, and pulmonary artery pressure. In contrast, capsaicin injected into the left ventricle did not alter airway diameter or aortic pressure, although heart rate and pulmonary artery pressure decreased but to a lesser extent than after right ventricular injection. After vagotomy, capsaicin had no effect on airway diameter or heart rate but aortic pressure and pulmonary artery pressure increased slightly. Results suggest that pulmonary receptors sensitive to capsaicin and accessible via the pulmonary circulation produce reflex bronchoconstriction. One possible function of this vagal reflex is to assist fluid movement from microvasculature to peribronchial space by reducing peribronchial pressure.

Animals↗

Reversal of 5HT-induced bronchoconstriction by PGI2: distribution of central and peripheral actions.

In anesthetized, mechanically ventilated, and vagotomized cats, we studied the distribution of the bronchodilatory effects of prostaglandin I2 (PGI2) in central and peripheral airways. In the intact-chest cat, bolus intravenous injection of PGI2 in a range of doses from 3 to 100 micrograms produced dose-dependent reversal of 5-hydroxytryptamine- (5HT) induced bronchoconstriction. Bronchodilatory effects were manifested by a pronounced decrease in central airways flow resistance, as estimated by measurement of lung resistance and by an increase in dynamic lung compliance (Cdyn). A similar distribution and magnitude of airway effects were produced by intravenous administration of PGE1 in a range of doses from 0.3 to 10 micrograms. PGI2 significantly reversed the frequency dependence of compliance induced by infusion of 5HT. The PGI2 metabolite, 6-keto-PGF1 alpha, was without effect on pulmonary mechanics. Comparison of right- versus left-heart administration of PGI2 did not point to a significant role of the bronchial circulation in the airway effects of PGI2. Comparison of the effects of PGI2 and PGE1 on cat bronchial and parenchymal strips contracted by 5HT showed both prostaglandins to have predominant action on bronchial smooth muscle with PGI2 being 3-10 times less active than PGE1. These data suggest that PGI2 has central airway bronchodilator activity, similar to, but less potent than PGE1. In addition, they suggest that PGI2 has significant dilator activity in certain peripheral areas of the lung, as well.

Animals↗

Basenji-Greyhound dog model of asthma: influence of atropine on antigen-induced bronchoconstriction.

To test the relative importance of cholinergic effects on the Basenji-Greyhound (BG) model of asthma, we administered Ascaris antigen to Ascaris-sensitive BG dogs without other treatment, and following intravenous atropine. Pulmonary resistance (RL) increased from 1.4 +/- 0.43 cmH2O . l-1 . s (mean + SE) to 26.0 +/- 5.21 after Ascaris antigen exposure in seven untreated dogs. In the same dogs pretreated with 0.2 mg/kg atropine, RL increased from 1.5 +/- 0.31 to 18 +/- 5.00. Atropine 0.4 and 1.0 mg/kg did not result in increased protection. Although 0.2 mg/kg atropine markedly inhibited the airway responses to both inhaled citric acid and methacholine, it only slightly prevented antigen-induced airway constriction. We conclude that in BG dogs, cholinergic pathways elicit bronchomotor responses to irritants but that the major component of antigen-induced bronchoconstriction is not cholinergically mediated.

Animals↗

Time course of the bronchoconstriction induced by inhaled histamine and methacholine.

Eleven asthmatic subjects inhaled doubling concentrations of histamine until a near sixfold increase in total pulmonary flow resistance had been reached. This last concentration (C6) of histamine and methacholine was administered on two subsequent separate visits. Specific lung conductance (sGL) dropped to 18.6 +/- 7.9 (SD) and 19.1 +/- 10.3% of initial value after histamine and methacholine, respectively (NS). Whereas the peak action occurred in a similar interval (1-4 min), the mean duration of the subsequent plateau, defined as values of sGL within 20% of the maximum fall was 16.8 +/- 9.8 min for histamine and 74.6 +/- 53.7 min for methacholine (P less than 0.01). The recovery phase from the end of the plateau to base line lasted 25.5 +/- 14.4 min for histamine and 56.7 +/- 38.3 min for methacholine (P less than 0.01). The duration of plateau and recovery phases were not linked with base-line sGL, maximum fall in sGL, or C6. We conclude that for the same induced bronchoconstriction methacholine has a more prolonged action than histamine.

Adolescent↗

Changes in flow-volume curve configuration with bronchoconstriction and bronchodilation.

Changes in the configuration of maximum expiratory flow-volume (MEFV) curves following mild degrees of bronchodilation or bronchoconstriction were studied in five normal and five asthmatic subjects. In a volume-displacement plethysmograph, MEFV curves were performed before and after inhalation of aerosolized isoproterenol (I) or histamine (H). Five filtered MEFV curves were averaged, and slope ratio vs. volume (SR-V) plots were obtained from averaged curves. Following I, maximal flows at 75% of the vital capacity (VC) were decreased in asthmatics but not in normal subjects. Flows at 50 and 25% of the VC increased in normal subjects and asthmatics, whereas VC's were unchanged. In asthmatics, sudden large decreases in flow (bumps) occurred at lower lung volumes following I. H reduced flows over the entire VC, with greater reductions occurring in asthmatics than in normals, particularly at low lung volumes. In asthmatics, VC was slightly reduced, and bumps in MEFV curve configuration occurred at higher lung volumes or were abolished entirely following H. A reduction in the amount of configurational detail appreciable in MEFV curves following histamine in asthmatics was best seen in SR-V plots. Following H, SR's decreased regularly with decreasing lung volume in all the asthmatics but in none of the normals. This was the single most striking finding of this study. Mild I- and H-induced perturbations of airway bronchomotor tone produced small but consistent changes in MEFV curve configuration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗