n(6)-cyclopentyladenosine and Hypersensitivity

The effect of the adenosine triphosphate sensitive K+ (K(ATP)) channel opener (3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-piperidinyl)-N-phenyl-1-benzopyran-6-sulphonamide (KCO912) on airway hyperresponsiveness induced using either a combination of allergen immunization (i.p.) followed by aerosol allergen challenge or immunization alone was investigated. Rabbits were immunized with Alternaria tenuis for the first 3 months of life. Airway responsiveness to histamine was measured 24 h before and after A. tenuis aerosol challenge. Fifteen minutes before the second challenge, rabbits were pre-treated with 10 microg of KCO912 or vehicle by inhalation. Allergen challenge induced airway hyperresponsiveness in vehicle pre-treated rabbits and pre-treatment with KCO912 abolished the airway hyperresponsiveness. The effect of KCO912 (10 microg) or vehicle on baseline airway hyperresponsiveness to the adenosine A(1) receptor agonist, cyclopentyl adenosine (CPA), induced by immunization with A. tenuis alone, was also assessed. Rabbits, immunized with A. tenuis alone, exhibited baseline airway hyperresponsiveness as demonstrated by an increase in airway resistance to CPA. Treatment with KCO912 did not alter the allergen-induced airway responsiveness to CPA. This study demonstrates that KCO912 can inhibit allergen-induced exacerbations of airway hyperresponsiveness.

Topics: Adenosine; Adenosine Triphosphate; Allergens; Alternaria; Animals; Antigens, Fungal; Benzopyrans; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Hypersensitivity; Piperidines; Potassium Channels; Rabbits

1. New Zealand White (NZW) rabbits were immunized within 24 h of birth with Alternaria tenuis in aluminium hydroxide (Al (OH)3) (i.p.) or sham immunized (saline plus Al (OH)3 i.p.) and subsequently injected with the allergen (i.p.) or sham-immunized for the next 3 months. At 3 months of age, baseline airway responsiveness was assessed using cyclo-pentyl adenosine (CPA). Bronchoalveolar lavage (BAL) was performed in all animals and samples of peripheral blood were collected from some animals for estimation of dexamethasone levels. In some animals, blood was collected at the end of the experiment and cellular function was assessed by measurement of ex vivo proliferation of mononuclear cells in response to phytohaemagglutinin (PHA). 2. Allergen immunization significantly increased baseline airway responsiveness to inhaled CPA (P<0.05) in comparison with sham-immunized animals, at 3 months after immunization. Dexamethasone (0.5 mg kg(-1) day(-1)) treatment for 1 month did not modify this established airway hyper-responsiveness to CPA. Dexamethasone treatment did not affect either total or differential cell numbers in BAL fluid during the 4 week period, although significant plasma levels of dexamethasone were achieved in dexamethasone treated animals. 3. Treatment of rabbits with dexamethasone (0.1 mg kg(-1) i.p.), 6 h prior to each allergen injection from the neonatal stage, significantly reduced baseline airway hyper-responsiveness to CPA measured at 3 months (P<0.05). There was no significant difference in either total or differential cell numbers in BAL fluid, or any difference in mitogen-induced proliferation of mononuclear cells between dexamethasone and vehicle treated rabbits. 4. These results suggest that introduction of glucocorticosteroids in early life can prevent baseline airway hyper-responsiveness to inhaled CPA in allergic rabbits. However, once established, such underlying airway hyper-responsiveness is difficult to resolve, even with prolonged treatment with glucocorticosteroids.

Topics: Adenosine; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Count; Cell Division; Dexamethasone; Disease Models, Animal; Female; Glucocorticoids; Hypersensitivity; Leukocytes, Mononuclear; Male; Phytohemagglutinins; Purinergic P1 Receptor Agonists; 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.

Topics: Adenosine; Adenosine Monophosphate; Airway Resistance; Animals; Bronchoconstriction; Female; Hypersensitivity; Lung; Lung Compliance; Male; Rabbits; Receptors, Purinergic P1