It has been previously proposed that
adenosine plays an important role in the pathogenesis of
asthma. The proposed mechanism of action for
nucleoside adenosine is to activate A(2B)
adenosine receptors (AR) and to indirectly modulate levels of mediators in the lung. In vivo data supporting the role of A(2B) AR in airway reactivity and
inflammation in allergic animal models are lacking. The present study describes the effects of a selective A(2B) AR antagonist,
CVT-6883 [3-ethyl-1-propyl-8-[1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl]-3,7-dihydropurine-2,6-dione], on airway reactivity and
inflammation in an allergic mouse model of
asthma. Mice were sensitized with ragweed (i.p.) on days 1 and 6 and challenged with 0.5% ragweed on days 11, 12, and 13. On day 14, airway reactivity to
5'-N-ethylcarboxamidoadenosine (
NECA),
AMP, or
allergen challenge was measured in terms of enhanced pause (Penh). Aerosolized
NECA elicited concentration-dependent increases in Penh, which were significantly attenuated by
CVT-6883 (0.4, 1.0, or 2.5 mg/kg i.p.). Aerosolized
AMP elicited significant increases in Penh in sensitized mice, and the effect was significantly attenuated by either
CVT-6883 (1 mg/kg i.p.) or
montelukast (1 mg/kg i.p.).
Allergen challenge induced late allergic response in sensitized mice, which was inhibited by
CVT-6883 (1 mg/kg i.p.).
Allergen challenge also increased the number of cells in bronchoalveolar lavage fluid obtained from sensitized mice, and that was reduced by either
CVT-6883 (6 mg/ml aerosolization for 5 min) or
theophylline (36 mg/ml aerosolization for 5 min). These results suggest that A(2B)AR antagonism plays an important role in inhibition of airway reactivity and
inflammation in this model of allergic
asthma.