Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells

Adenosine has potent effects on both the cardiovascular and immune systems. Exposure of tissues to adenosine results in increased vascular permeabilit y and extravasation of serum proteins. The mechanism by which adenosine bri ngs about these physiological changes is poorly defined. Using mice deficie nt in the Ag adenosine receptor (A(3)AR), we show that increases in cutaneo us vascular permeability observed after treatment with adenosine or its pri ncipal metabolite inosine are mediated through the A3AR. Adenosine fails to increase vascular permeability in mast cell-deficient mice, suggesting tha t this tissue response to adenosine is mast cell-dependent. Furthermore, th is response is independent of activation of the high-affinity IgE receptor (Fc epsilon R1) by antigen, as adenosine is equally effective in mediating these changes in FceR1 P-chain-deficient mice. Together these results suppo rt a model in which adenosine and inosine induce changes in vascular permea bility indirectly by activating mast cells, which in turn release vasoactiv e substances. The demonstration in vivo that adenosine, acting through a sp ecific receptor, can provoke degranulation of this important tissue-based e ffector cell, independent of antigen activation of the high-affinity IgE re ceptor, supports an important role for this nucleoside in modifying the inf lammatory response.