Pharmacology and Therapeutics of Bronchodilators Revisited.

Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because many of these have no better efficacy than existing classes of bronchodilator and often have unacceptable safety profiles. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of ß 2-adrenoceptors (ß 2-ARs) on airway smooth muscle with ß 2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting ß 2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" containing fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a number of so-called "bifunctional drugs" having two different primary pharmacological actions in the same molecule are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD. SIGNIFICANCE STATEMENT: Since our last review in 2012, there has been considerable research to identify novel classes of bronchodilator drugs, to further understand how to optimize the use of the existing classes of bronchodilator, and to better understand the role of bifunctional drugs in the treatment of asthma and chronic obstructive pulmonary disease.

The anti-proliferative effects of adiponectin on human lung adenocarcinoma A549 cells and oxidative stress involvement.

Adiponectin (Acrp30) plays an important role in energy metabolism and inflammation. Recently, in vivo serum Acrp30 levels have been reported to be correlated to risk of developing several types of cancers such as lung cancer, and in vitro studies have demonstrated a role for Acrp30 in the control of cell proliferation and survival. However, the molecular effects of Acrp30 on lung cancer have not yet been clearly defined. In the present study, we investigated the effects of different concentrations of Acrp30 on the A549 human alveolar epithelial cell line, an in vitro model of lung adenocarcinoma. A549 cells were exposed to various concentrations of Acrp30 and successively, proliferation, apoptosis and oxidative stress were evaluated by MTT test, caspase activity assay, flow-cytometry and western blotting analysis. Our results demonstrated that Acrp30 causes, in a time- and dose-dependent manner, a reduction of cell viability and duplication together with an increase in cell apoptosis rate. In addition, we found that Acrp30 induces an increase of lipid peroxidation evaluated by TBARS assay and a concomitant reduction of nitric oxide release, both markers of cellular oxidative stress. Taken together, our data on A549 cells provides new insight into potential involvement of Acrp30 on physio-pathologic mechanisms of lung diseases through interference with proliferation, apoptosis and oxidative status.

Combining long-acting bronchodilators with different mechanisms of action: A pharmacological approach to optimize bronchodilation of equine airways.

The ultra long-acting ß2 -adrenoceptor agonist olodaterol plus the ultra long-acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration-Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (1:1). The single agents elicited a significant (p < .05) concentration-dependent reduction in the EFS-induced contractility, that was synergistically improved (CI 0.18) when administered in combination (0.9 logarithms more potent, 24% more effective than the monocomponents). The drugs mixture allowed a reduction in the concentration of olodaterol from ≃1 to ≃2.3 logarithms. A favorable CRI was detected also for tiotropium bromide, whose concentration can be reduced ≃1 logarithm at medium effect levels, remaining positive up to submaximal relaxant effect in the presence of olodaterol. The combination of tiotropium bromide/olodaterol allows the reduction in the concentration of the monocomponents to achieve airway smooth muscle relaxation, thus potentially decreases the risk of adverse events when these drugs are used to treat severe asthmatic horses.

Effects of chronic administration of ß-blockers on airway responsiveness in a murine model of heart failure.

Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates ß-adrenoceptors (ß-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a ß-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. ß2-ARs and G-protein-ßAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, ß2-AR mRNA level was significantly decreased in HF groups (-48.73 ± 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 ± 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 ± 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 ± 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; HF, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; MET, Emax: 85.43 ± 6.80%, pD2: 6.95 ± 0.59, P < 0.001). In HF, the down-regulation of pulmonary ß-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of ß-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases.

LABAs in asthmatic children: highlights and new inside.

International asthma guidelines recommend increasing the dose of ICS or adding leukotriene modifiers or the use of long-acting inhaled beta2-agonists (LABAs) in combination with inhaled corticosteroids (ICS) when uncontrolled asthma occurs in adult and children in treatment with low-dose inhaled corticosteroids. However, in children, the effects of this last treatment option are unclear because there are few studies on the efficacy and safety of these drugs in pediatric age. Furthermore, salmeterol is licensed for use in children over 4 years and formoterol in children of more than 6 years. Finally, recent data provides evidence that repeated bronchoconstriction induces epithelial cell stress that may lead to remodeling and these findings may have potential implications for asthma management, particularly for LABAs treatment in the future.

Prolonged-release pirfenidone in patients with pulmonary fibrosis as a phenotype of post-acute sequelae of COVID-19 pneumonia. Safety and efficacy.

INTRODUCTION: One of the major concerns with post-acute sequelae of COVID-19 (PASC) is the development of pulmonary fibrosis, for which no approved pharmacological treatment exists. Therefore, the primary aim of this open-label study was to evaluate the safety and the potential clinical efficacy of a prolonged-release pirfenidone formulation (PR-PFD) in patients having PASC-pulmonary fibrosis. METHODS: Patients with PASC-pulmonary fibrosis received PR-PFD 1800 mg/day (1200 mg in the morning after breakfast and 600 mg in the evening after dinner) for three months. Blood samples were taken to confirm the pharmacokinetics of PR-PFD, and adverse events (AEs) were evaluated monthly using a short questionnaire. Symptoms, dyspnea, and pulmonary function tests (spirometry, diffusing capacity for carbon monoxide, plethysmography, and 6-min walk test [6MWT]) were evaluated at baseline, and one and three months after having started the PR-PFD treatment. RESULTS: Seventy subjects with mild to moderate lung restriction were included. The most common AEs were diarrhea (23%), heartburn (23%), and headache (16%), for which no modifications in the drug study were needed. Two patients died within the first 30 days of enrolment, and three opted not to continue the study, events which were not associate with PR-PFD. Pulmonary function testing, 6MWT, dyspnea, symptoms, and CT scan significantly improved after three months of treatment with PR-PFD. CONCLUSION: In patients with PASC pulmonary fibrosis, three months' treatment with PR-PFD was safe and showed therapeutic efficacy. Still, it remains to be seen whether the pulmonary fibrotic process remains stable, becomes progressive or will improve.

Emerging inhaled bronchodilators: an update.

Bronchodilators remain central to the symptomatic management of chronic obstructive pulmonary disease and asthma, and, for this reason and also because the patent protection of many bronchodilators has expired, several companies have reinitiated research into the field. The only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities. The incorporation of once-daily dose administration is an important strategy for improving adherence and is a regimen preferred by most patients. A variety of beta(2)-agonists and antimuscarinic agents with longer half-lives and inhalers containing a combination of several classes of long-acting bronchodilator are currently under development. The present article reviews all of the most important compounds under development, describing what has been done and discussing their genuine advantage.

Novel long-acting bronchodilators for COPD and asthma.

An important step in simplifying asthma and chronic obstructive pulmonary disease (COPD) management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence and is a regimen preferred by most patients, which may also lead to enhancement of compliance, and may have advantages leading to improved overall clinical outcomes. Once-daily beta2-agonists or ultra long-acting beta2-agonists (LABAs) such as carmoterol, indacaterol, GSK-159797, GSK-597901, GSK-159802, GSK-642444 and GSK-678007 are under development for the treatment of asthma and COPD. Also some new long-acting antimuscarinic agents (LAMAs) such as aclidinium, LAS-35201, GSK656398, GSK233705, NVA-237 (glycopyrrolate) and OrM3 are under development. In any case, the current opinion is that it will be advantageous to develop inhalers containing combination of several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimens as much as possible. Consequently, several options for once-daily dual-action ultra LABA+LAMA combination products are currently being evaluated. A different approach is to have a dimer molecule in which both pharmacologies are present (these molecules are known as M3 antagonist-beta2 agonist (MABA) bronchodilators). The advent of a successful MABA product will revolutionize the field and open the door for a new range of combination products.

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

Clinical effect of corticosteroids in asthma-affected horses: A quantitative synthesis.

BACKGROUND: There are limited findings from low-powered studies based on few number of subjects with equine asthma. Furthermore, no studies have been performed to assess a meaningful clinically detectable impact of corticosteroids in equine asthma. OBJECTIVES: To assess and compare the clinical effect of inhaled and systemic corticosteroids in equine asthma and identify a quantitative clinical score suitable to assess the Minimal Important Difference (MID), expressed as the Minimally Clinically Detectable Difference (MCDD). STUDY DESIGN: Pair-wise and network meta-analysis. METHODS: Literature searches for studies on corticosteroid therapy in equine asthma were performed. The risk of publication bias was assessed by Funnel plots and Egger's test. The effect on changes in clinical scores vs. control was analysed via random-effects models and Bayesian networks. RESULTS: Corticosteroids significantly improved the clinical condition (Standardised Mean Difference: -1.52, 95% CrI -2.07 to -0.98; P<0.001 vs. control). No difference was detected between inhaled and systemic corticosteroids with regard to the changes in clinical scores (Relative Effect: 0.08, 95% CrI -1.45 to 1.32; P = 0.8). An Improved clinically Detectable Equine Asthma Scoring System (IDEASS) indicated that corticosteroids improved the clinical condition of asthmatic horses by 30% compared with controls (IDEASS value: -2.36, 95% CI -3.39 to -1.33; P<0.001). A one-point change in IDEASS represented the MCDD in equine asthma. MAIN LIMITATIONS: Moderate quality of evidence for systemic corticosteroids. CONCLUSIONS: Inhaled corticosteroids are effective in improving the clinical condition of horses with equine asthma and prevent exacerbations. Systemic corticosteroids should be used only in selected cases with symptomatic airway hyperresponsiveness during exacerbation. IDEASS requires further validation but may represent a suitable approach to rank the level of asthma severity and assess the clinical effect of pharmacotherapy in horses with equine asthma.

Benralizumab for the treatment of asthma.

Benralizumab is a humanized monoclonal antibody directed at the a subunit of the interleukin-5 receptor (IL-5R) that is under clinical development. The binding of benralizumab with the alpha chain of IL-5R results in inhibition of hetero-oligomerization of alpha and beta subunits and thus no signal transduction occurs. Consequently, this inhibition prevents proliferation of eosinophils and basophils and the cascade of events following it. Several pivotal trials have documented that benralizumab reduces asthma exacerbation rates with a significant increase in time to the next exacerbation, statistically improves prebronchodilator forced expiratory volume in 1 second (FEV1) and disease-specific health-related quality of life, and is well tolerated in patients with severe asthma and blood eosinophil counts greater than or equal to 150 cells/mcL.

Pharmacological treatments in asthma-affected horses: A pair-wise and network meta-analysis.

BACKGROUND: Equine asthma is a disease characterised by reversible airflow obstruction, bronchial hyper-responsiveness and airway inflammation following exposure of susceptible horses to specific airborne agents. Although clinical remission can be achieved in a low-airborne dust environment, repeated exacerbations may lead to irreversible airway remodelling. The available data on the pharmacotherapy of equine asthma result from several small studies, and no head-to-head clinical trials have been conducted among the available medications. OBJECTIVES: To assess the impact of the pharmacological interventions in equine asthma and compare the effect of different classes of drugs on lung function. STUDY DESIGN: Pair-wise and network meta-analysis. METHODS: Literature searches for clinical trials on the pharmacotherapy of equine asthma were performed. The risk of publication bias was assessed by funnel plots and Egger's test. Changes in maximum transpulmonary or pleural pressure, pulmonary resistance and dynamic lung compliance vs. control were analysed via random-effects models and Bayesian networks. RESULTS: The results obtained from 319 equine asthma-affected horses were extracted from 32 studies. Bronchodilators, corticosteroids and chromones improved maximum transpulmonary or pleural pressure (range: -8.0 to -21.4 cmH2 O; P<0.001). Bronchodilators, corticosteroids and furosemide reduced pulmonary resistance (range: -1.2 to -1.9 cmH2 O/L/s; P<0.001), and weakly increased dynamic lung compliance. Inhaled ß2 -adrenoreceptor (ß2 -AR) agonists and inhaled corticosteroids had the highest probability of being the best therapies. Long-term treatments were more effective than short-term treatments. MAIN LIMITATIONS: Weak publication bias was detected. CONCLUSIONS: This study demonstrates that long-term treatments with inhaled corticosteroids and long-acting ß2 -AR agonists may represent the first choice for treating equine asthma. Further high quality clinical trials are needed to clarify whether inhaled bronchodilators should be preferred to inhaled corticosteroids or vice versa, and to investigate the potential superiority of combination therapy in equine asthma.

Effect of formoterol/budesonide combination on arterial blood gases in patients with acute exacerbation of COPD.

BACKGROUND: Patients with severe chronic airway obstruction might suffer dangerous hypoxemia after administration of a beta-agonist despite bronchodilation. METHODS: We first compared the acute effects on gas exchange of two doses of formoterol Turbuhaler (9 and 18 microg) in 10 patients with acute exacerbation of COPD. Afterwards, we compared the acute effects of formoterol Turbuhaler 9 microug with those of formoterol/budesonide combination in a single inhaler (Turbuhaler) 9/320 microg in 10 other patients with acute exacerbation of COPD. Finally, we compared the changes in PaO(2) induced by formoterol Turbuhaler 9 microg or formoterol/budesonide combination in a single inhaler (Turbuhaler) 9/320 microg with those in FEV(1) in 10 other patients with acute exacerbation of COPD. Each agent was given on separate days, and the patients' arterial blood gases were measured at baseline and at intervals of 120 min. RESULTS: Small but statistically significant declines in PaO(2) were found after administration of both formoterol 9 and 18 microg. In the second group of patients, formoterol 9 microg alone again induced a significant decrease in PaO(2). However, the simultaneous administration of budesonide 320 microg significantly reduced the acute effect of formoterol on PaO(2). In a third group of 10 patients we confirmed a small but significant decrease in PaO(2) after formoterol alone and the reduction of this effect when budesonide was administered simultaneously. Moreover, we also documented that addition of budesonide amplified the fast onset of action of formoterol. CONCLUSIONS: These results suggest that when treating patients suffering from acute exacerbation of COPD with formoterol, it is prudent to check their arterial blood gases. In any case, combined administration of formoterol and budesonide reduces the potential for acute effects of formoterol on blood-gas tensions.

Comparison of the acute effect of tiotropium versus a combination therapy with single inhaler budesonide/formoterol on the degree of resting pulmonary hyperinflation.

In 20 COPD patients (FEV(1) < or =65% predicted, IC<80% predicted), we evaluated changes in the degree of pulmonary hyperinflation after acute administration of tiotropium 18 microg or budesonide/formoterol 320/9 microg. The study consisted of a screening visit and two study days separated by at least one week. Functional parameters were measured before and 30, and 120 min after inhalation of single study drug. Both tiotropium and budesonide/formoterol induced significant changes in functional parameters after 30 and 120 min. However, the impact of tiotropium on the degree of pulmonary hyperinflation was larger than that of budesonide/formoterol, although only differences in IC and TGV between the two treatments were significant (P<0.05), at least after 120 min, whereas those in RV were not significant. The documentation that tiotropium is able to modify IC even after an acute administration indicates its capacity of influencing expiratory flow limitation in a very fast manner and this is an important finding. In fact, changes in IC after bronchodilators in patients with COPD with expiratory flow limitation at rest may represent an objective tool for prescribing these drugs to attain symptomatic improvement and better quality of life, even in the absence of a significant increase in FEV(1).

5-HT modifiers as a potential treatment of asthma.

Increased levels of free 5-HT have been shown to be present in the plasma of symptomatic asthmatic patients compared with levels in asymptomatic patients. In addition, free 5-HT has been shown to correlate positively with clinical status and negatively with pulmonary function. These findings suggest that 5-HT might play a role in the pathophysiology of acute asthma. Accordingly, modifiers of the 5-HT transmitter system such as compounds that affect the 5-HT transporter, prejunctional 5-HT receptors or postsynaptic 5-HT receptors might represent a novel treatment of asthma.

Immune sensitization of equine bronchus: glutathione, IL-1beta expression and tissue responsiveness.

BACKGROUND: Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-kappaB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1beta. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1beta and airway hyperresponsiveness. METHODS: We have examined the effect of passive sensitization on IL-1beta mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 microM), were used to quantify IL-1beta mRNA. Other tissues were used to study the effect of EFS (3-10-25 Hz). RESULTS: Mean IL-1beta mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1beta mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. CONCLUSION: Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1beta mRNA expression and responsiveness to EFS of passively sensitized bronchi.

Fluticasone furoate/vilanterol combination for the treatment of COPD and asthma.

The critical role of the combination therapy of an inhaled corticosteroid (ICS) and a long-acting ß-adrenoceptor agonist (LABA) in the treatment of patients suffering from asthma and also severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations explains why there is a strong interest within the pharmaceutical industry in developing a once-daily ICS/LABA fixed-dose combination (FDC), in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy, and also to overcome the loss of patent protection. GlaxoSmithKline and Theravance have developed an inhaled FDC of the ICS fluticasone furoate (FF) and the LABA vilanterol (VI) as a once-daily treatment for asthma and COPD. FF/VI, by simplifying the dosing schedule, allows, for the first time, a shift from twice-daily to once-daily treatment, with an acceptable safety and tolerability profile that is consistent with the ICS/LABA class. The decision to prescribe FF/VI rather than another ICS/LABA FDC is likely to be based on the patient's preference for the inhaler device, their ability to use the device correctly and the convenience of once-daily dosing frequency as well as comparative costs with other combination products. However, further studies are required to specifically assess these possibilities.

Aclidinium/formoterol fixed-dose combination for the treatment of chronic obstructive pulmonary disease.

This review will be focused on the development of aclidinium bromide/formoterol fumarate (ACLI/FORM) fixed-dose combinations (FDC) that have been granted marketing authorization by the European Commission to be used as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). ACLI/FORM FDC has been studied in 2 pivotal trials involving over 3,400 patients with COPD, in which it was compared with ACLI alone, FORM alone and placebo. The addition of FORM to ACLI resulted in greater bronchodilation than FORM or ACLI alone. ACLI/FORM FDC was also shown to increase the percentage of patients who had an improvement in symptoms and health-related quality of life compared with monotherapies. The frequency of side effects reported with ACLI/FORM FDC was low and their nature did not raise any major safety concern.

Characterization of adenosine receptors involved in adenosine-induced bronchoconstriction in allergic rabbits.

1. Recent work has suggested that adenosine may be involved in asthma via the activation of A1 receptors. However, the role of the recently cloned A3 receptor in airways is largely unknown. In the present study, we have investigated the role of the A3 receptor in adenosine-induced bronchoconstriction in allergic rabbits. 2. Aerosol challenge of antigen (Ag) immunized rabbits with the adenosine precursor, adenosine 5'-monophosphate (AMP), resulted in a dose-dependent fall in dynamic compliance (Cdyn). The maximum fall in Cdyn in these rabbits was significantly greater than that in litter matched, sham immunized animals (P < 0.05). However, there was no significant difference in the maximum increase in airways resistance (Rt) between Ag and sham immunized rabbits (P > 0.05). 3. Aerosol challenge of Ag immunized rabbits with cyclopentyl-adenosine (CPA) (A1-receptor agonist) elicited a dose-dependent fall in Cdyn in Ag immunized rabbits and the maximum fall in Cdyn in these rabbits was significantly greater than that observed in sham immunized rabbits (P < 0.05). Similarly, CPA induced dose-dependent increases in R1 in Ag immunized rabbits whereas sham immunized rabbits failed to respond to CPA within the same dose range. The maximum increase in RL in Ag immunized rabbits was significantly greater than that of sham immunized rabbits (P < 0.05). 4. Aerosol challenge of either Ag or sham immunized rabbits with the A3 agonist aminophenylethyladenosine (APNEA) did not elicit dose-dependent changes in either RL or Cdyn. Moreover, there was no significant difference in the maximum response, measured by either parameter, between the two animal groups (P > 0.05). 5. These data provide further evidence for a role of the A1 receptor in the airways, but do not support a role for the A3 receptor in adenosine-induced bronchoconstriction in the allergic rabbit.