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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of a Specific and Selective A_2B Adenosine Receptor Antagonist on Adenosine Agonist AMP and Allergen-Induced Airway Responsiveness and Cellular Influx in a Mouse Model of Asthma

Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (S.J.M., A.N.); Department of Pharmacology, East Carolina University, Greenville, North Carolina (M.F.); and CV Therapeutics, Inc., Palo Alto, California (H.Z., L.B., D.Z.)

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_2BAR antagonism plays an important role in inhibition of airway reactivity and inflammation in this model of allergic asthma.

Address correspondence to: Dr. S. Jamal Mustafa, Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV 26506. E-mail: smustafa{at}hsc.wvu.edu

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