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PubMed1985

Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release.

Adenosine, when it is administered by inhalation to asthmatic subjects, is a potent bronchoconstrictor, although its mechanism of action is not known. Since adenosine has been demonstrated to potentiate IgE-dependent mediator release from mast cells, we have investigated the possible relationship between adenosine-induced bronchoconstriction and release of mast cell mediators in 14 asthmatic subjects. In the first study the effect of the putative mast cell-stabilizing drug cromolyn sodium (SCG) was observed on the dose-related changes in SGaw and FEV1 produced by inhaled adenosine and histamine in seven subjects. Inhaled SCG (20 mg) had no effect on the airway responses to histamine. In contrast SCG significantly protected against adenosine-induced bronchoconstriction in four of the seven subjects as reflected by a decrease in the airway response to the highest concentrations of adenosine, from 65 +/- 8% to 12 +/- 3% (mean +/- SEM) for SGaw and 31 +/- 7% to 8 +/- 3% for FEV1. Those three subjects whose adenosine response was unaffected by SCG had received regular SCG until 12 hr before the studies. In a separate study on eight subjects, a single inhalation of adenosine, causing a maximum 61 +/- 4% fall in SGaw at 10 min, had no significant effect on circulating levels of histamine, neutrophil chemotactic factor, or cyclic AMP. Together these two studies suggest that bronchoconstriction produced by adenosine is not a consequence of enhanced mast cell-mediator release and that the inhibitory effects of SCG occur by a mechanism other than through mast cell stabilization.

Adenosine↗

PubMed1985

The effect of theophylline and enprofylline on allergen-induced bronchoconstriction.

The effect on the allergen-induced immediate and late bronchoconstriction of theophylline and enprofylline (3-propylxanthine), a new xanthine derivative with negligible ability to antagonize adenosine, was studied in nine patients with asthma. The patients were challenged three times at weekly intervals with the same dose of allergen. FEV1 and SGaw were followed up to 6 hours after challenge. The drugs were administered intravenously. Placebo was always administered on the first occasion. Theophylline and enprofylline were administered on test days 2 and 3 with a double-blind, randomized crossover technique. One hour before the allergen challenge, a loading dose was administered during 60 minutes followed by a constant infusion during 6 hours. The loading infusion was 7.2 mg/kg of theophylline and 2.7 mg/kg of enprofylline. The maintenance dose was 74 mg/hr and 71 mg/hr, respectively. Both theophylline and enprofylline caused a minor initial bronchodilatation. Theophylline and enprofylline slightly but significantly attenuated the immediate bronchoconstricting reaction after allergen inhalation. Theophylline and enprofylline had a significant attenuating effect on the late bronchial reaction. The mean plasma level of theophylline was 0, 10.8, 10.5, and 10.5 mg/L at 0, 1, 4, and 7 hours after the start of the loading infusion, respectively. The corresponding mean plasma levels of enprofylline were 0, 2.6, 2.7, and 2.7 mg/L. Theophylline and enprofylline caused headache in one patient. Two patients developed nausea and vomiting during the enprofylline infusion. The present data suggest that adenosine receptor antagonism may not be the main mode of action of xanthines in inhibiting bronchoconstriction after single dose antigen challenge.

Adult↗

PubMed1987

Mechanism of leukotriene D4-induced bronchoconstriction in normal subject.

Leukotriene (LT) D4 is a potent constrictor of human airways and a putative mediator of asthma. However, its mechanism of action in man has not been established. In the present study we sought to determine the role of upper airway reflexes, cholinergic pathways, and cyclooxygenase products of arachidonic acid metabolism in mediating LTD4-induced bronchoconstriction in man. Six normal subjects underwent bronchoprovocation testing with LTD4 after pretreatment with either aerosolized phosphate-buffered saline, aerosolized atropine (1.5 mg), aerosolized lidocaine (80 to 160 mg), or oral indomethacin (50 mg three times daily for 10 doses). Specific airway conductance (SGaw), the flow rate at 30% of vital capacity from a partial forced expiratory maneuver (V30P), and the FEV1 were measured at each concentration of LTD4. We calculated the provocative concentration of LTD4 required to produce a 35% fall in SGaw (PC35SGaw) or a 30% fall in V30P (PC30V30P) and the slope of the LTD4 dose-response curve. Atropine increased baseline SGaw 49% (p less than 0.01) and V30P 43% (p less than 0.005). Atropine also increased the PC35SGaw and PC30V30P and increased the slope of the LTD4 dose-response curve. However, neither of these opposing effects was significant. Lidocaine had no effect on either baseline function or the airway response to LTD4. Indomethacin produced small decreases in baseline V30P (12%) and FEV1 (3%) (p less than 0.05 for both), but it too had no effect on the airway response to LTD4. These results indicate that the bronchoconstriction produced by aerosolized LTD4 in normal subjects is not mediated by cyclooxygenase products of arachidonic acid metabolism or irritant receptors in the upper airways. Although cholinergic pathways may play some role, the data suggest that bronchoconstriction results, at least in part, from a direct effect of LTD4 on airway smooth muscle.

Adult↗

PubMed1987

The effect of an oral leukotriene antagonist L-649,923 on histamine and leukotriene D4-induced bronchoconstriction in normal man.

We have studied the effect of prior treatment with an oral leukotriene (LT) antagonist L-649,923, on histamine and LTD4-induced bronchoconstriction in 12 normal male subjects in a double-blind, placebo-controlled, randomized, crossover trial. L-649,923 had no effect on histamine-induced bronchoconstriction but antagonized LTD4-induced bronchoconstriction, causing a mean shift to the right of the dose-response curves of 3.8-fold. This study demonstrates that LT antagonism is possible and safe in man and that LTD4-inhalation challenge testing can be used to detect LT antagonism.

Adult↗

PubMed1990

Effects of oral cetirizine, a selective H1 antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma.

The protective efficacy of oral cetirizine, a selective and potent H1-receptor antagonist, against the immediate bronchoconstrictive response to allergen inhalation and exercise challenge was evaluated in 16 subjects with stable, predominantly mild asthma. The subjects underwent double-blind, crossover pretreatments in randomized order in two separate protocols with (1) three daily oral doses of 20 mg of cetirizine and placebo, followed by allergen inhalation, and (2) single oral doses of cetirizine (5, 10, and 20 mg), albuterol (4 mg), and placebo, followed by exercise with cold-air inhalation. Cetirizine failed to decrease bronchial sensitivity to inhaled allergen in eight of 10 subjects. Neither cetirizine nor albuterol uniformly inhibited exercise-induced bronchoconstriction. Serum concentrations of cetirizine were consistent with systemic H1-blocking activity. Modest bronchodilation occurred after administration of cetirizine and albuterol before exercise but not after the third dose of cetirizine in the allergen protocol. One subject developed moderate drowsiness during multiple dosing with cetirizine. Thus, cetirizine, in the doses studied, is not uniformly effective in preventing allergen- or exercise-induced bronchoconstriction. Histamine is one of many mediators participating in immediate asthmatic responses, and selective H1 antagonists do not completely block these airway events. However, cetirizine may still clinically benefit some patients with asthma, such as patients with allergic rhinitis or urticaria.

Administration, Oral↗

PubMed1990

Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma.

We have investigated the ability of salbutamol to protect against bronchoconstriction induced by methacholine, histamine, and adenosine 5'-monophosphate (AMP) in nine subjects with asthma. In a double-blind, placebo-controlled study, salbutamol, 2.5 mg administered by nebulization, increased the geometric mean provocation concentrations of methacholine, histamine, and AMP required to produce a 20% decrease in FEV1 from 0.3 to 2.2, 0.4 to 3.8, and 4.0 to 106.7 mg/ml after placebo and active treatment, respectively (p less than 0.01). Thus, this dose of beta 2-adrenoceptor agonist displaced the concentration-response curves for methacholine, histamine, and AMP to the right in a parallel fashion by 8.8 (0.6 to 29.3)-, 10.3 (1.4 to 33)-, and 26.6 (1.5 to 76.6)-fold, respectively, the difference between the results for AMP and those for histamine and methacholine being statistically significant (p less than 0.01). For six of the nine subjects studied, salbutamol displaced the concentration-response curve for AMP to the right by greater than 50-fold. There was no correlation between bronchodilatation and protection against bronchoconstriction induced by any of the agonists. We conclude that salbutamol protects against bronchoconstriction provoked by methacholine and histamine by functional antagonism, whereas with AMP, an additional activity is demonstrable, possibly involving inhibition of mast cell-mediator release.

Adenosine Monophosphate↗

PubMed2005

Airway immunopathology of asthma with exercise-induced bronchoconstriction.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a common cause of symptoms in a subgroup of asthmatic subjects. The pathobiology that makes this group of asthmatic subjects susceptible to bronchoconstriction after a brief period of exercise remains poorly understood. OBJECTIVE: We sought to determine whether there are differences in lower airway inflammation and production of cytokines and eicosanoids between asthmatic subjects with and without EIB. METHODS: Two distinct groups of asthmatic subjects based on a priori definitions were identified, one with moderate-to-severe EIB and the other without significant bronchoconstriction after exercise challenge. Both groups met the definition of asthma on the basis of bronchodilator response, bronchial hyperresponsiveness, or both. A comparative immunopathology study was conducted by using induced sputum to identify differences in lower airway inflammation and production of cytokines and eicosanoids. RESULTS: The groups had similar baseline lung function and bronchodilator response and did not have any asthma exacerbations within the prior year. The concentration of columnar epithelial cells was markedly higher in the group with EIB (1.4 x 10(5) vs 2.9 x 10(4) cells/mL, P=.01). The concentration of eosinophils was higher in the group with EIB (3.6 x 10(4) vs 4.9 x 10(3) cells/mL P=.04). Cysteinyl leukotrienes (CysLTs; 727.7 vs 151.9 pg/mL, P=.01) and the ratio of CysLTs to prostaglandin E(2) (1.85 vs 1.04, P=.002) in the airways were higher in the group with EIB. CONCLUSION: Injury to the airway epithelium, overexpression of CysLTs, relative under production of prostaglandin E(2), and greater airway eosinophilia are distinctive immunopathologic features of asthma with EIB.

Adult↗

PubMed2006

Exhaled nitric oxide and airway caliber during exercise-induced bronchoconstriction.

Data on the relationship between exercise-induced bronchoconstriction (EIB) and exhaled nitric oxide (NO) in adult patients with asthma are controversial. It is unclear whether endogenous NO may act as either a protective or stimulatory factor in the airway response to exercise or whether changes in exhaled NO simply reflect acute narrowing of the airway. The aim of this study was to assess the changes in the fraction of exhaled nitric oxide (FE(NO)) before and after exercise challenge in patients with asthma and to analyze the relationship between FE(NO) and airway obstruction. Twenty-five non-smoking, steroid-naïve, atopic, adult patients with mild persistent asthma and 12 non-smoking, nonatopic, healthy subjects (control group) performed an exercise challenge on a cycloergometer, with monitored ventilation. FEV1 and FE(NO) were measured at baseline and 1, 5, 10, 15 and 20 minutes after the exercise challenge. Eleven of the asthmatic patients had exercise-induced bronchoconstriction (EIB group) and the remaining 14 did not (non-EIB group). Baseline FE(NO) was higher in the EIB and non-EIB asthmatic groups than in the control group. In the EIB group, FE(NO) was significantly lower 5, 10 and 15 minutes after exercise, and the changes in FE(NO) correlated with variation in FEV1 10 and 15 min after exercise. A significant correlation between baseline FE(NO) and maximal post-exercise decrease in FEV1 was found in asthmatic patients (EIB group). In conclusion, exhaled nitric oxide levels transiently decrease during exercise-induced bronchoconstriction in adult patients with asthma. Baseline FE(NO) might predict the airway obstruction resulting after exercise.

Adolescent↗

PubMed2005

Ryanodine receptors in muscarinic receptor-mediated bronchoconstriction.

Ryanodine receptors (RyRs), intracellular calcium release channels essential for skeletal and cardiac muscle contraction, are also expressed in various types of smooth muscle cells. In particular, recent studies have suggested that in airway smooth muscle cells (ASMCs) provoked by spasmogens, stored calcium release by the cardiac isoform of RyR (RyR2) contributes to the calcium response that leads to airway constriction (bronchoconstriction). Here we report that mouse ASMCs also express the skeletal muscle and brain isoforms of RyRs (RyR1 and RyR3, respectively). In these cells, RyR1 is localized to the periphery near the cell membrane, whereas RyR3 is more centrally localized. Moreover, RyR1 and/or RyR3 in mouse airway smooth muscle also appear to mediate bronchoconstriction caused by the muscarinic receptor agonist carbachol. Inhibiting all RyR isoforms with > or = 200 microM ryanodine attenuated the graded carbachol-induced contractile responses of mouse bronchial rings and calcium responses of ASMCs throughout the range of carbachol used (50 nM to > or = 3 microM). In contrast, inhibiting only RyR1 and RyR3 with 25 microM dantrolene attenuated these responses caused by high (>500 nM) but not by low concentrations of carbachol. These data suggest that, as the stimulation of muscarinic receptor in the airway smooth muscle increases, RyR1 and/or RyR3 also mediate the calcium response and thus bronchoconstriction. Our findings provide new insights into the complex calcium signaling in ASMCs and suggest that RyRs are potential therapeutic targets in bronchospastic disorders such as asthma.

Animals↗

PubMed1988

The relationship between exposure duration and sulfur dioxide-induced bronchoconstriction in asthmatic subjects.

The purpose of this study was to determine the shortest duration of exposure to 1.0 ppm sulfur dioxide (SO2) sufficient to induce bronchoconstriction significantly greater than that observed with exposure to clean air (CA) in exercising SO2-sensitive asthmatics. Asymptomatic, nonmedicated, male asthmatics (n = 12) with airway hyperresponsiveness to both methacholine and SO2 were exposed in a chamber (20 degrees C, 40% relative humidity) for 0.0, 0.5, 1.0, 2.0 and 5.0 min to both CA and 1.0 ppm SO2 on separate days (10 exposures). Just prior to each exposure, subjects walked on a treadmill in CA for 5 min at a predetermined speed/elevation to elicit a target ventilation of about 40 L/min, i.e., a brisk pace up a slight incline. After this walk, subjects rapidly entered an adjoining exposure chamber containing either CA or SO2 and immediately walked at the same speed/elevation for the specified exposure duration. Subjects then rapidly exited the chamber. Specific airway resistance (SRaw) and ratings of respiratory symptoms associated with asthma [shortness of breath/chest discomfort (SB/CD) and wheezing (WHZ)] were measured prior to any exercise and following each exposure. Postexposure SRaw and symptom ratings increased with increased exposure duration in SO2; postexposure SRaw also was increased with increased exposure duration in CA but to a lesser extent. After adjusting for the CA response, significantly greater SO2-induced bronchoconstriction was observed for the 2.0 and 5.0 min exposures as indicated by substantially greater increases in SRaw and substantially higher ratings of respiratory symptoms. The authors conclude that with the above exposure conditions, on average, SO2-sensitive asthmatics exhibit significant bronchoconstriction at exposure durations of 2.0 min or more.

Adult↗

PubMed2003

Bronchoconstriction during cross-country skiing: is there really a refractory period?

PURPOSE: The asthmatic airway responds to exercise by bronchodilation (BD) during and bronchoconstriction (BC) after exercise. A refractory period induced by an initial exercise challenge that provides protection against BC during a subsequent exercise bout has also been observed. However, no studies examining during-exercise response or refractoriness during long-duration field exercise by elite athletes have been performed. This study examined airway response and refractoriness during approximately 42-min cross-country ski time trial preceded by a 6- to 9-min 2.5-km high-intensity warm-up ski. METHODS: Eighteen elite athletes cross-country skied seven successive 2.5-km loops. Spirometry was performed pre- and at 5, 10, and 15 min post loop 1; loops 2-7 were treated as a race (XCR) with maneuvers performed within 20 s after loops 2-6 and serially for 15 min after lap 7. RESULTS: Nine of 18 subjects demonstrated a >or=10% fall from baseline in FEV(1) (EIB+): five after lap 1 and four during or after laps 2-7. FEV(1) for EIB+ athletes during XCR was not different from post lap 1 FEV. Only one EIB+ subject demonstrated significant refractoriness. Four EIB+ athletes had a less than 10% fall in FEV after the initial 2.5-km exercise challenge but developed EIB (>or=10% fall) during the subsequent 6 x 2.5 km XCR exercise challenge. FEF(25-75) falls mirrored FEV(1), but demonstrated greater BD during XCR. CONCLUSION: Bronchoconstriction occurs in athletes during prolonged exercise and may thus influence performance. Variability in bronchial hyperresponsiveness onset and the lack of significant refractoriness in our study cohort of athletes is consistent with an exercise bronchoconstrictive dysfunction that is different than frank asthma and is yet to be clearly defined.

Adolescent↗

PubMed1984

The action of prazosin and propylene glycol on methoxamine-induced bronchoconstriction in asthmatic subjects.

The effect of 1 mg inhaled prazosin on bronchoconstriction induced by methoxamine was investigated in seven asthmatic subjects. Prazosin caused significant inhibition of the methoxamine-induced bronchoconstriction in six of the seven patients. These findings suggest that methoxamine produces bronchoconstriction in asthmatic subjects via stimulation of alpha-adrenoceptors. In previous studies propylene glycol has been used as a vehicle for delivery of prazosin. This substance was found to cause significant inhibition of methoxamine effects and to shift the dose response curve to histamine to the right in four of seven patients.

Adult↗

PubMed1988

The influence of ipratropium bromide and sodium cromoglycate on benzalkonium chloride-induced bronchoconstriction in asthma.

1. Benzalkonium chloride, an antibacterial preservative that is added to nebuliser solutions, has been shown to cause bronchoconstriction when inhaled by asthmatic subjects. 2. To investigate the potential role of reflex and mast cell-dependent mechanisms in the pathogenesis of bronchoconstriction produced by benzalkonium chloride we examined the effects of ipratropium bromide and sodium cromoglycate on this response in both concentration-response and time-course studies in nine asthmatic subjects. 3. Pretreatment with inhaled ipratropium bromide (1 mg) and sodium cromoglycate (40 mg) displaced the benzalkonium chloride concentration-response curves to the right by a mean 2.2 fold and 3.1 fold respectively. 4. Ipratropium bromide and sodium cromoglycate markedly attenuated the airway response to benzalkonium chloride throughout the 45 min time course period, inhibiting the overall response by 56% and 78% respectively. 5. We conclude that benzalkonium chloride provokes bronchoconstriction in asthmatic subjects through a combination of mast cell activation and stimulation of peripheral and central neural pathways.

Adult↗

PubMed1990

Effect of formoterol, a long-lasting beta 2-adrenoceptor agonist, against methacholine-induced bronchoconstriction.

1. The effects of a new long-acting inhaled beta 2-adrenoceptor agonist aerosol formoterol (12 micrograms), on FEV1, and on methacholine-induced bronchoconstriction, were compared with those of terbutaline (250 micrograms) and placebo in 12 midly asthmatic subjects. 2. PC20, the concentration of methacholine needed to cause a 20% fall in baseline FEV1, was determined 2 and 5 h after formoterol, terbutaline and placebo on separate days. Baseline PC20 was determined on a different day. 3. Compared with terbutaline and placebo, formoterol hastened recovery from methacholine-induced bronchoconstriction, and significantly increased mean PC20 (by 2.2- and 2.9-fold at 2 and 5 h respectively). 4. Thus, formoterol has a protective effect against methacholine-induced bronchoconstriction which lasts for at least 5 h.

Adrenergic beta-Agonists↗

PubMed1985

Effects of verapamil and sodium cromoglycate on bronchoconstriction induced by isocapnic hyperventilation.

Twenty-four patients who were known to develop bronchoconstriction in response to isocapnic hyperventilation (IH) took part in a double-blind, placebo-controlled trial to assess the effects of verapamil (5 mg) and sodium cromoglycate (SCG) 20 mg in the prevention of IH-induced bronchoconstriction. Both drug and placebo were inhaled in dry powder form and responses were assessed by serial measurements of forced expiratory volume in 1 sec (FEV1). Sodium cromoglycate was shown to offer significant protection whereas verapamil powder provoked bronchoconstriction in over 40% of patients and these patients appeared to be those with more marked degrees of bronchial reactivity.

Asthma, Exercise-Induced↗

PubMed1988

Comparative study of the effects of nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) on adenosine-induced bronchoconstriction in asthmatic subjects.

The effect of nedocromil sodium (4 mg; 7.8 X 10(-6) M) on adenosine-induced bronchoconstriction was compared with that of a higher dose of sodium cromoglycate (10 mg; 24.1 X 10(-6) M). Eleven allergic asthmatic patients (mean age 26.28 +/- 12.21 years) were studied. Adenosine (0.03-4.00 mg) was administered as nebulized aerosol. The dose of adenosine producing a 20% change in FEV1(PD20) was calculated from the individual semi-logarithmic dose-response curves. Patients were studied on 4 separate days. On the first day the adenosine challenge was performed; on subsequent days patients were pretreated (20 min before challenge) with either placebo or test drug (nedocromil sodium 2 x 2 mg or sodium cromoglycate 2 x 5 mg) administered by pressurized aerosol in a randomized, double-blind manner. Statistical analysis was performed by two-way analysis of variance. Neither sodium cromoglycate nor nedocromil sodium showed a significant bronchodilator effect. In patients treated with placebo, inhalation of adenosine produced a dose-related bronchoconstriction with a geometric mean PD20 of 0.42 mg. After drug administration the mean PD20 values were 1.29 mg with sodium cromoglycate and 2.30 mg with nedocromil sodium. Both drugs produced a significant increase in mean PD20 value in comparison with placebo and baseline (P less than 0.01). These results demonstrate that nedocromil sodium (4 mg) is significantly more potent than a larger dose of sodium cromoglycate (10 mg) in inhibiting adenosine-induced bronchoconstriction (P less than 0.05).

Adenosine↗

PubMed1989

The inhibitory effect of azelastine hydrochloride on histamine- and allergen-induced bronchoconstriction in atopic asthma.

We have examined the effect of azelastine, a new H1 histamine receptor antagonist, against bronchoconstriction induced by histamine and allergen. Twelve mild, atopic asthmatics each underwent two histamine and two allergen concentration-response inhalation challenges 4 hr after treatment with either 8.8 mg of azelastine or a matched placebo. Following azelastine the dose of histamine required to provoke a 20% fall in FEV1 (PD20 histamine) rose, from a geometric mean of 0.31 mg/ml to greater than 13.2 mg/ml. Azelastine also significantly inhibited allergen-induced bronchoconstriction, the PD20 allergen rising from 9.3 cumulative breath units (c.b.u.) to greater than 47.9 c.b.u., a greater than 5-fold increase. We conclude that azelastine effectively inhibits both histamine and allergen-induced bronchoconstriction, with considerably greater potency against histamine.

Administration, Inhalation↗

PubMed1991

Inhibitory effect of inhaled procaterol on anaphylactic bronchoconstriction and thromboxane A2 production in guinea-pigs.

This study was designed to examine whether an inhaled beta 2-agonist, procaterol, inhibits thromboxane A2 (TXA2) production induced by antigen challenge in passively sensitized guinea-pigs in vivo. Antigen-induced bronchoconstriction was markedly inhibited by pre-treatment with procaterol. Inhaled procaterol significantly reduced in a dose-dependent manner the increment in TXB2 concentration in bronchoalveolar lavage fluid obtained 5 min after antigen challenge. Aerosol administration of procaterol significantly inhibited bronchoconstriction induced by inhaled histamine. These results suggest that inhalation of procaterol has an inhibitory effect on antigen-induced TXA2 production as well as a protective effect against bronchoconstriction induced by bronchoactive agents.

Administration, Inhalation↗