Adenosine A2Breceptors as therapeutic targets

Recent evidence indicates that A2B receptors mediate cellular functions with potential clinical relevance. Both A2A and A2B receptors mediate vasodilation, and the receptor type involved depends on the vascular bed and species studied. In some experimental models, A2B-induced vasodilation is mediated by the endothelium, but it is unclear whether this vasodilation is due to nitric oxide or whether A2B receptors also mediate direct vascular smooth muscle relaxation. A2B receptors expressed in smooth muscle cells inhibit their growth, raising the possibility that these receptors play a role in the vascular remodeling process observed in hypertension and atherosclerosis. A2B receptors are also expressed in neurons, and there are several examples of these receptors mediating neuroexcitatory actions, including potentiation of neurotransmitter release. The highest expression of A2B receptors is found throughout the intestinal tract. During diarrheal processes, neutrophils recruited into intestinal crypts release a soluble “neutrophil-derived secretagogue,” which then increases intestinal secretion. It is now known that this neutrophil product is AMP, which is then converted to adenosine to activate A2B receptors expressed in intestinal epithelium. It was also recently found that activation of human mast cells by adenosine is mediated by A2B receptors. Mast cell activation is involved in adenosine-induced bronchoconstriction in asthmatics, suggesting that A2B receptors are involved in this process. Our understanding of the functional role of A2B receptors is hindered by the lack of selective agonist and antagonist of this receptor type. Recent studies suggest the feasibility of developing A2B antagonists. Such agents may prove useful in the treatment of diarrheal diseases and in asthma. Drug Dev. Res. 45:198–206, 1998.