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PubMed1982

Differing mechanisms for leukotriene d4-induced bronchoconstriction in guinea pigs following intravenous and aerosol administration.

Leukotriene D4 (LTD4) when administered intravenously or by aerosol to guinea pigs produced changes in pulmonary mechanics including a decrease in dynamic compliance and an increase in pulmonary resistance. The effects of intravenous LTD4 (0.5 microgram kg-1) were short lived and abolished by pretreatment of the animal with either cyclooxygenase inhibitors, a thromboxane synthetase inhibitor (OKY 1555) or an SRS-A antagonist (FPL 55712). These findings suggest that bronchoconstriction produced by the intravenous infusion of LTD4 at 0.5 microgram kg-1 is due to the release of thromboxane A2. However, in animals treated with indomethacin, LTD4 at higher doses (greater than 0.8 microgram kg-1) still elicited a bronchoconstriction which could be blocked by FPL 55712. Nebulization of 0.1 - 1.0 microgram of LTD4 into the lung produced prolonged changes in pulmonary mechanics which were inhibited by FPL 55712 and were potentiated by indomethacin. LTD4, therefore, when administered by aerosol produced effects on the lung which were not mediated by cyclooxygenase products. Responses to nebulized rather than intravenous LTD4 in the guinea pig may more closely resemble those seen in human tissues.

Aerosols↗

PubMed1984

Effects of a contractile prostaglandin antagonist (L-640,035) upon allergen-induced bronchoconstriction in hyperreactive rats and conscious squirrel monkeys.

The effects of an antagonist of contractile prostanoids, L-640,035 (3-hydroxymethyl-dibenzo[b,f]thiepin-5-dioxide) upon antigen-induced bronchoconstriction have been studied in inbred rats with non-specific bronchial hyperreactivity and in conscious squirrel monkeys. L-640,035 was a potent inhibitor of antigen-induced dyspnea (ED50 3.1 mg/kg p.o.) in inbred rats pretreated with methysergide (3 micrograms/kg i.v.) but produced no significant inhibition in untreated rats. Administration of L-640,035 (10 mg/kg p.o.) to conscious squirrel monkeys exposed to aerosols of ascaris antigen markedly inhibited changes in pulmonary resistance (RL) and dynamic compliance (CDYN). At a lower dose (1 mg/kg p.o.) the inhibition of changes in CDYN were similar but the effects on RL were reduced. It was concluded first that contractile prostanoids may be important mediators of antigen-induced bronchoconstriction and secondly that L-640,035 may be effective in human allergic asthma.

Airway Resistance↗

PubMed1990

OKY-046 inhibits anaphylactic bronchoconstriction and reduces histamine level in bronchoalveolar lavage fluid in sensitized guinea pigs.

We investigated the effects of OKY-046, a potent and selective thromboxane A2 (TxA2) synthetase inhibitor, on anaphylactic bronchoconstriction and release of chemical mediators into airway lumen in sensitized guinea pigs in vivo. OKY-046 dose-dependently inhibited antigen-induced anaphylactic bronchoconstriction with or without mepyramine, a histamine H1 antagonist. In the presence of mepyramine, OKY-046 (300 mg/kg, p.o.) elicited significant reductions in histamine (1 min) and TxB2 increases (1-15 min) in bronchoalveolar lavage (BAL) fluid but significantly increased the plasma level of 6-keto-PGF1 alpha, a stable PGI2 metabolite, after antigen challenge. On the contrary, indomethacin only significantly reduced increases in TxB2 levels. These results suggest that the antiasthmatic effect of OKY-046 is probably due to inhibition of TxA2 synthesis and suppression of histamine release via a PGI2 shunting mechanism.

6-Ketoprostaglandin F1 alpha↗

PubMed1976

Metabolic changes in exercise-induced and methacholine-induced bronchoconstriction.

Metabolic and physiological responses to graded exercise and methacholine challenge were investigated in asthmatics with or without exercise-induced bronchoconstriction. The results showed that after methacholine challenge, free fatty acid levels increased only in patients with exercise-induced asthma, while they increased in both groups of asthmatics after treadmill exercise. No significant changes were noted in plasma lactic acid levels, ventilation, or oxygen consumption among the groups studied. These data suggest that asthmatics with exercise-induced bronchoconstriction may differ from other asthmatics in some of their metabolic responses.

Adolescent↗

PubMed1979

Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes, and preservatives in a population of perennial asthmatics.

Forty-five patients with moderately severe perennial bronchial asthma were challenged by ingestion of: acetylsalicyclic acid (ASA); 4 azo dyes (tartrazine, sunset yellow, amaranth, and ponceau); 3 non-azo dyes (erythrosine, brilliant blue, and indigotin); sodium benzoate (NaB); parahydroxybenzoic acid (OHBA); butylated hydroxyanisole (BHA); and butylated hydroxytoluene (BHT). A fall in forced expiratory volume is one second (FEV1) greater than 25% from baseline was considered positive. Seven patients who gave an unequivocal history of aspirin intolerance were not challenged with ASA; an additional 13 had positive open challenges to ASA, giving an apparent incidence of aspirin sensitivity of 20/45. The presence of nasal polyps, simusitis, or the regular use of corticosteroids, either singly or in combination, was not associated with an increased incidence of reactions to ASA. Significant bronchoconstriction to open challenges with agents other than ASA was less frequent. Positive open challenges to all substances except aspirin were followed by double-blind challenges which were positive in only 3 instances: 1 each with erythrosine, ponceau, and NaB/OHBA. Our findings confirm that ASA intolerance is relatively common but suggest on the other hand that reactions to dyes and preservatives are uncommon cause of clinically significant bronchoconstriction in moderately severe perennial asthmatics.

Adolescent↗

PubMed1980

Prevention of antigen-induced bronchoconstriction by lodoxamide ethyl, a new orally active antiallergic drug.

Lodoxamide ethyl, an orally active drug with pharmacologic activity similar to that of cromolyn sodium, blocks passive cutaneous anaphylaxis (PCA) in rats and antigen-induced bronchoconstriction in guinea pigs and monkeys. Its effectiveness in preventing antigen-induced airway obstruction was studied in 12 asymptomatic asthmatic adults with immediate skin test sensitivity to ragweed, Alternaria, or animal dander. The dose required to reduce the forced expiratory volume in 1 sec (FEV1) by 20% (PD20) was determined by dosimeter bronchoprovocation challenge with the appropriate antigen. At 1-wk intervals each subject received either placebo of 1, 3, or 10 mg drug in a randomized, double-blind fashion 30 min prior to starting bronchoprovocation challenge. On average, 1 mg increased the PD20 fivefold, 3 mg about sixfold, and 10 mg about 27-fold. Dose-related side effects began 10 min after drug and lasted up to 40 min. Thus the oral administration of lodoxamide ethyl was effective in preventing antigen-induced bronchoconstriction, and both the beneficial effects and side effects are dose related.

Adult↗

PubMed1984

Plasma histamine and catecholamines during carbachol-induced bronchoconstriction in normal subjects.

To determine (1) whether changes in plasma histamine occurred during provoked bronchospasm and (2) if so, whether such changes could be related to variations in plasma catecholamines, venous plasma histamine and catecholamines were measured during a dose-response carbachol challenge in eight healthy volunteers. A significant rise in plasma histamine was observed, whereas induced bronchoconstriction was small, 80% +/- 4% of initial specific airway conductance. There was no further increase in plasma histamine, whereas induced bronchoconstriction became more marked (70%, 60%, and 50% of specific airway conductance initial value). Plasma catecholamines did not change throughout the study. We conclude that mast cell degranulation occurs during a carbachol challenge, and that the variations in plasma histamine are not related to changes in plasma catecholamines.

Adult↗

PubMed1985

Activation of neutrophils and monocytes after allergen- and histamine-induced bronchoconstriction.

To determine whether neutrophils and monocytes are activated after allergen-induced asthma, changes in the expression of complement (C3b) receptors were measured by use of the rosette technique. There was a time-dependent increase in the percentages of neutrophil and monocyte rosettes in 13 asthmatic patients for up to 60 min after allergen-inhalation challenge. This was preceded by elevations in the concentrations of serum neutrophil chemotactic activity and reductions in the FEV1. These changes were not observed in seven asthmatic patients who had histamine-induced bronchoconstriction. The present findings support the view that inflammatory cells are activated after allergen-induced asthma and that this may be the result of the release of mast cell-associated mediators rather than the consequence of bronchoconstriction per se.

Adult↗

PubMed1988

Inhibition of antigen-induced bronchoconstriction by a new calcium antagonist, gallopamil: comparison with cromolyn sodium.

We have previously demonstrated partial attenuation of antigen-induced bronchoconstriction by aerosolized verapamil (Chest 1985;88:176-80). In the present investigation, we studied the effect of a new calcium antagonist, gallopamil, on allergic bronchial reactivity and compared it to that of cromolyn sodium. Nine asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma were studied on 4 different days, without and after pretreatments with aerosolized placebo, gallopamil (10 mg), or cromolyn sodium (20 mg) solution, in a single-blind, randomized, crossover design. Bronchial reactivity was measured as the cumulative provocative dose of ragweed antigen in breath units (PD35) that caused a 35% decrease in specific airway conductance (SGaw). Baseline SGaw was comparable on control, placebo-, gallopamil- and cromolyn sodium-treatment days. The airway deposition dose of gallopamil and cromolyn sodium was calculated at 1.05 mg and 2.1 mg, respectively. Neither cromolyn sodium nor gallopamil had a significant effect on mean SGaw. Mean +/- PD35 on control and placebo-treatment days was 0.54 +/- 0.95 and 0.23 +/- 0.17 breath units, respectively. Aerosolized gallopamil and cromolyn sodium increased the mean PD35 to 56 +/- 41 and 24 +/- 35 breath units, respectively (p less than 0.05). Gallopamil completely inhibited the antigen-induced bronchoconstriction in six (67%) subjects, whereas cromolyn sodium was totally effective in two of the nine (22%) subjects. These results demonstrate that aerosolized gallopamil inhibits allergic bronchial reactivity with efficacy comparable or better than cromolyn sodium.

Adult↗

PubMed1988

Increased responsiveness to histamine after propranolol in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol.

Eight nonsmoking subjects with asthma, nonresponsive to the bronchoconstrictive effect of oral propranolol, were studied. The airway response to increasing concentrations of histamine aerosol was assessed by measuring FEV1. The threshold provocative dose of histamine needed to cause a 20% fall in starting FEV1 (PD20) was measured by log dose-response curve. Histamine challenge was performed in duplicate after premedication with placebo or 40 mg of propranolol on separate days. The mean starting FEV1 did not change significantly after placebo and after propranolol administration. The mean PD20 values after propranolol (0.37 mg/ml and 0.32 mg/ml, respectively, for the first and the second challenge) were significantly lower (p less than 0.01) than mean control PD20 values (1.36 mg/ml and 1.48 mg/ml, respectively, for the first and the second challenge). These results indicate that propranolol increases airway responsiveness to histamine, even in those subjects with asthma in whom propranolol has little bronchoconstrictive effect.

Adult↗

PubMed1989

Histamine and leukotrienes release in bronchoalveolar fluid during plicatic acid-induced bronchoconstriction.

Bronchoalveolar lavage (BAL) was performed before and 10 minutes after inhalation challenge with plicatic acid in five patients with red cedar asthma. There was a significant release of histamine and leukotriene E4 into the BAL fluid in all the patients after challenge. Inhalation challenge with methacholine in six patients with nonoccupational asthma and inhalation challenge with plicatic acid in two subjects without asthma did not result in the release of mediators in the BAL fluid. These studies provide direct evidence that plicatic acid-induced bronchoconstriction was accompanied by increased levels of histamine and leukotriene E4 release, whereas a nonimmunologic induction of bronchoconstriction did not induce such local mediator release. BAL may provide a useful means of studying the pathogenesis of occupational asthma caused by exposure to low-molecular-weight compounds.

Adolescent↗

PubMed1990

Effects of prostacyclin on bronchoconstriction and neutropenia induced by inhaled platelet-activating factor in man.

We studied the effects of prostacyclin (PGI2) on the airway responses to platelet-activating factor (PAF) in a randomized and crossover study in eight normal subjects. PGI2 or diluent (glycine buffer) was continuously infused on 2 separate days. Two breaths of PAF (21 micrograms) were inhaled three times every 15 minutes and airflow at 30% of vital capacity from partial flow-volume curves (Vp30) was measured. PGI2 (4 ng/kg/min) had no effect on Vp30 or blood pressure, whereas heart rate increased from 70.3 +/- 3.9 to 73.7 +/- 4.0 beats/min (mean +/- SEM; p less than 0.01). Two subjects did not complete the study because of transient hypotension. PGI2 had no effect on PAF-induced bronchoconstriction with maximal decreases in Vp30 of 42.0 +/- 8.0% (p less than 0.01) during PGI2 and 49.8 +/- 14.2% (p less than 0.02) during diluent infusion. Ex vivo platelet aggregation to PAF (10(-9) to 10(-7) mol/L) was significantly inhibited by PGI2. Circulating neutrophils decreased from 4.7 +/- 0.9 x 10(9)/L to 1.5 +/- 0.3 x 10(9)/L (p less than 0.05) 5 minutes after the first PAF inhalation during diluent infusion, whereas there was no significant change with PGI2. Thus, PGI2 does not influence PAF-induced bronchoconstriction in man despite causing marked inhibition of ex vivo PAF-induced platelet aggregation and preventing the fall of neutrophils.

Administration, Inhalation↗

PubMed1986

Comparative effects of various calcium entry blockers and anti-asthmatic compounds on antigen-induced bronchoconstriction in rat and histamine release from rat mast cells.

The effects of four calcium entry blockers (diltiazem, nifedipine, mesudipine and verapamil) were studied on antigen-induced bronchoconstriction in sensitized rats and histamine release from rat mast cells, in comparison with compounds frequently used in atopic patients (theophylline, isoproterenol, disodium cromoglycate, ketotifen and clemastine). The four Ca2+ entry blockers produced a dose-related inhibition of the IgE-dependent bronchoconstriction in rat whereas the other drugs exhibited a weak effect or even were inactive. 48/80-induced histamine release was antagonized by nifedipine, verapamil and ketotifen. On the contrary, diltiazem, mesudipine, theophylline, isoproterenol, disodium cromoglycate and clemastine were not able to interfere with this release process. These data may suggest an important role of both extra- and intracellular calcium in such phenomena.

Animals↗

PubMed1985

SK&F 88046: inhibition of thromboxane-induced bronchoconstriction in anesthetized dogs.

In addition to its well-described pro-aggregatory action, thromboxane A2 (TxA2) has been shown to be a potent bronchoconstrictor. The present study was designed to evaluate whether SK&F 88046 [N,N'-bis-7-(3-chlorobenzeneaminosulfonyl)-1,2,3,4- tetrahydroisoquinolyl disulfonylimide] had any inhibitory effects against canine bronchoconstriction induced by U-44069, a functional TxA2 mimic. Bronchopulmonary responses were measured by computer analyses in spontaneously breathing, pentobarbital-anesthetized mongrel dogs. In a dose range of 0.3-3.0 micrograms/kg i.v., U-44069 produced potent, dose-related increases in pulmonary airway resistance (RL) and decreases in dynamic lung compliance (CDYN), which were indicative of severe bronchoconstriction. The onset of agonist activity was prompt (1-2 min) and recovery usually occurred within 5-10 min. Pretreatment with varying doses of SK&F 88046 (1, 3 and 5 mg/kg) as a 10 min i.v. infusion, produced a significant inhibition of the RL and CDYN effects of U-44069. In addition, SK&F 88046, as well as UK 37248 (dazoxiben), a thromboxane synthetase inhibitor, was effective vs. arachidonic acid-induced decreases in CDYN; however, SK&F 88046 failed to alter significantly bronchopulmonary effects induced by other known bronchoconstrictors, e.g., PGF2 alpha, PGD2, histamine or acetylcholine. Therefore, SK&F 88046 represents an antagonist of TxA2-mediated changes in airway mechanics in the anesthetized dog.

Acetylcholine↗

PubMed1990

Recombinant human C5a-induced bronchoconstriction in the guinea-pig: a histamine independent mechanism.

Recombinant human C5a (rHuC5a), produced by a synthetic gene expressed in Escherichia coli, causes a decrease in dynamic lung compliance and an increase in pulmonary resistance when injected intravenously in anesthetized mechanically ventilated guinea pigs over a dose range of 5-20 micrograms/kg. Intravenous injection of rHuC5a also caused an immediate decrease in mean arterial blood pressure followed by a transient increase. The purpose of this study was to determine the mediators responsible for these effects. To assess the role of histamine, plasma levels of histamine were monitored and the effects of the H1 antagonist pyrilamine were assessed. rHuC5a caused a significant increase in plasma histamine. However, the H1 antagonist did not alter the maximum or the time course of the bronchoconstrictor response indicating that histamine did not play a major role. The LTD4 antagonist L-649,923 did not inhibit the rHuC5a-induced bronchoconstriction whereas the cyclo-oxygenase inhibitor indomethacin did. Thus, to assess the role of cyclo-oxygenase products, plasma levels of thromboxane (TX) B2, prostaglandin (PG) D2 and PGF2 alpha were monitored after injection of rHuC5a. In addition, guinea pigs were treated with either the TX synthetase inhibitor U-63557A or with the TX receptor antagonist SQ 29,548. rHuC5a challenge caused an increase in plasma concentrations of TXB2, PGD2 and PGF2 alpha which peaked before the maximum of the bronchoconstriction. SQ 29,548 significantly inhibited the maximum of the bronchoconstrictor response, whereas U-63557A did not inhibit the maximum but did inhibit the time course of the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Effect of nasal continuous positive airway pressure on methacholine-induced bronchoconstriction.

Bronchial hyper-responsiveness is a cardinal feature of asthma. To determine whether nasal continuous positive airway pressure (NCPAP) influences airway smooth muscle in response to exogenous stimuli, we examined the effect of NCPAP on aerosolized methacholine-induced bronchoconstriction in 16 stable asthmatic patients. The dose-response curve for each subject was measured by a log transformation and linear regression analysis as well as a formula fitted to the data points to obtain values for a (slope) and b (position). The PD20FEV1 significantly increased in patients receiving 8 cmH2O of NCPAP by one doubling dose compared with that in patients using sham pressure. NCPAP shifted the dose-response curves to be flatter, deviated upwards and to the right. The coefficient a, indicating bronchial reactivity, was significantly lower in patients receiving NCPAP. The coefficient b, indicating the bronchial sensitive threshold, was higher after applying NCPAP. In contrast, coefficients a and b did not change in subjects with sham pressure. NCPAP also significantly enhanced the bronchodilator effect of inhaled salbutamol in response to methacholine-induced bronchoconstriction. In summary, we have shown that NCPAP therapy improves bronchial smooth reactivity with an increase in PD20FEV1 and a reduction in the bronchial reactivity and bronchial sensitivity. Therefore, NCPAP may provide an adjuvant therapy in patients with acute bronchial asthma.

Acute Disease↗

PubMed2006

Aerosolised hyaluronic acid prevents exercise-induced bronchoconstriction, suggesting novel hypotheses on the correction of matrix defects in asthma.

Hyaluronic acid (HA), a biopolymer, member of the family of the glycosaminoglicanes (GAGs) is one of the major natural components of the connective amorphous matrix. The lungs, together with skin and intestine, contain >50% of HA of the body: it provides to several biologic functions and presents the unique capacity to link and retain a particularly relevant number of water molecules. Since other GAGs have been proven to be provided with anti-asthmatic properties and HA has been employed with positive results by intra-tracheal instillation in experimental models of lung emphysema and COPD, we have explored the efficacy of the pre-administered aerosol of HA (compared to placebo) in preventing in asthmatic patients the bronchoconstriction induced by a challenge test such as that obtained with muscular exercise. In a randomised, cross-over, single-blind study design, saline as placebo (P) or HA have been administered by aerosol, in two non-consecutive days, 30 min prior to the beginning of the challenge (10 min free running), to 14 patients (13-36 years old; 7 teenagers, 7 young adults; 11 males, 3 females; 12 allergic, 2 non-allergic), all suffering from mild bronchial asthma. The bronchoconstrictive effect induced by the muscular exercise has been relevant and statistically significant. With the P pre-treatment, the average FEV1 measured 5 min after the end of exercise was reduced by 36.14% from the baseline FEV1. Pre-treatment with HA determined a partial but clear-cut protection of the FEV1 impairment due to the challenge: the average post-challenge FEV1 resulted to be 12.43% less than the pre-challenge baseline value. No significant difference was observed in the level of HA protection in the subgroup of teenagers when compared to that of young adults. The protection induced by HA, when compared with P, resulted particularly significant by the statistical point of view (p < 0.0001). We conclude that aerosol HA administration significantly reduces the bronchial hyper-reactivity to muscular exercise in asthmatics. Such effect could be attributed to the correction of the pathological remodelling, one of the main features of asthma: a correction which could be attributed to the unique physicochemical properties of this major component of the loose connective amorphous matrix of the airways, which is undoubtedly involved in the remodelling process.

Adjuvants, Immunologic↗

PubMed1987

Respiratory impedance in normal humans: effects of bronchodilatation and bronchoconstriction.

Total respiratory resistance and reactance from 3 to 30 Hz were determined by the method of forced random noise oscillation in 12 normal male subjects before and after bronchodilatation and bronchoconstriction induced by deep breaths of aerosols of isoproterenol and atropine and of methacholine and histamine. Isoproterenol and atropine induced small decreases in total respiratory resistance at most frequencies, and isoproterenol decreased resonant frequency slightly (P less than 0.01). After administration of both methacholine and histamine, resonance frequency increased (P less than 0.01) and total respiratory resistance became more frequency-dependent, increasing mainly in the lower frequency range. In six of the subjects, we attempted to produce central deposition of methacholine by rapid, shallow breathing and peripheral deposition of the drug by slow, deep breathing. Only two subjects had suggestive evidence of central bronchoconstriction. No difference was noted, however, in the impedance behavior with either type of breathing. In awake humans, impedance analysis does not seem to distinguish between central and peripheral airway constriction.

Adult↗