Several lines of evidence support the hypothesis that adenosine contributes to asthma. Inhaled adenosine provokes bronchoconstriction in asthmatics, but not in nonasthmatics. This process appears to be mediated by mast cell activation, because it can be blocked by antihistamines and inhibitors of mast cell activation. Inhaled adenosine evokes release of mast cell mediators in bronchoalveolar lavage fluid, including histamine, prostaglandin DZ, and tryptase, a specific mast cell marker. Also, adenosine potentiates the immunological activation of mast cells in vitro, including rat peritoneal mast cells, mouse bone marrow-derived mast cells, human lung mast cells, and the human mast cell line HMC-1. The receptor subtype that mediates this activation differs between mast cell type, but preliminary evidence suggests that human lung mast cells express A26 receptors. An argument against the contribution of adenosine in asthma has been the "enprofylline paradox." This xanthine (3-(n-propylyl)xanthine) i s as effective an antiasthmatic as theophylline (1,3-dimettiyl xanthine) but was initially thought not to be an adenosine receptor antagonist. More recent evidence has confirmed that enprofylline blocksA2B receptors with a Ki (7 KM) similar to that of theophylline (13 pLM) and well within its therapeutic plasma levels (5-25 pM). This finding, we believe, resolves the enprofylline paradox and supports the hypothesis that adenosine, through A26 receptor activation, contributes to asthma. Preliminary evidence suggests that A26 receptors are indeed present in human lung mast cells. A26 receptors, therefore, may be a potential target for the development of antiasthmatic drugs.