Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models.
BACKGROUND Inhaled adenosine causes bronchoconstriction in asthmatics and may modulate inflammatory cell activity. Elevated adenosine levels occur in the lungs after antigen challenge of asthmatics. OBJECTIVES The aim of this study was to investigate whether the bronchoconstrictor effects of the adenosine derivative, 5'-AMP, were associated with altered migration of inflammatory cells into the airways using a sensitized atopic guinea-pig model previously shown to display a bronchoconstrictor response. Comparisons were made with the effects of inhaled antigen. METHODS Airway responses of conscious sensitized guinea-pigs to inhalation exposures of 5'-AMP were determined by whole body plethysmography as the change in specific airway conductance (sGaw). Influx of leucocytes into the airways was determined by bronchoalveolar lavage (BAL). RESULTS 5'-AMP caused bronchoconstrictor airway responses in sensitized animals. Dose-dependent infiltration of inflammatory cells into the lungs occurred 1 h after 5'-AMP exposure. No bronchoconstriction or cell influx was seen in unsensitized guinea-pigs. Exposure to ovalbumin (OA) also caused influx of inflammatory cells. Twenty-four hours after an OA exposure, 5'-AMP produced no bronchoconstriction. The P1-receptor antagonists, 8-PT and 8-SPT, inhibited the 5'-AMP-induced bronchoconstriction, indicating that the bronchoconstriction seen in sensitized animals is mediated by A1 or A2 receptors. They had no effect on the cell influx, whereas the A3 antagonist, MRS-1220, significantly inhibited cellular infiltration, suggesting mediation through A3 receptors. At 24 h after an OA challenge and accompanying the cellular influx, there was airway hyper-responsiveness to the bronchoconstriction by histamine. In contrast, no hyper-responsiveness to histamine was seen 1 h after 3 mM or 24 h after 300 mM 5'-AMP. CONCLUSIONS 5'-AMP caused a rapid migration of eosinophils and macrophages into the airways only in sensitized guinea-pigs, and this was blocked by the A3 antagonist MRS-1220. This was not associated with bronchial hyper-reactivity to histamine.