Molecular approach to adenosine receptors: Receptor-mediated mechanisms oftissue protection

Adenosine accumulation during ischemia and inflammation protects tissues fr om injury. In ischemic tissues adenosine accumulates due to inhibition of a denosine kinase, and in inflamed tissues adenosine is formed from adenine n ucleotides that are released from many cells including platelets, mast cell s, nerves, and endothelium. Nucleotides are rapidly converted to adenosine by a family of ecto-nucleotidases including CD39 and CD73. Activation of A( 1) and possibly A(3) adenosine receptors (ARs) protects heart and other tis sues by preconditioning through a pathway including protein kinase C and mi tochondrial K-ATP channels. Activation of A(2A) receptors limits reperfusio n injury by inhibiting inflammatory processes in neutrophils, platelets, ma crophages and T cells. Adenosine produces proinflammatory responses mediate d by receptors that vary among species; A(3) and A(2B) receptors mediate de granulation of rodent and human or canine mast cells, respectively. Novel a denosine receptor subtype-selective ligands have recently been developed. T hese include MRS 1754 (A(2B) blocker), MRS1220 (ALI blocker), MRE 3008F20 ( human A(3) blocker), MRS1523 (rat A(3) blocker), and ATL146e (A(2A) agonist ), These new pharmacologic tools will help investigators to sort out how ad enosine protects tissues from injury and to identify new therapeutic agents that hold promise for the treatment of inflammatory and ischemic diseases.