Activation of adenosine A2α receptors inhibits mast cell degranulation and mast cell-dependent vasoconstriction

Objective: Adenosine and inosine accumulate in tissue during periods of ischemia and both molecules have been shown to degranulate mast cells in the hamster cheek; pouch via activation of an A(3) receptor. An A(2)-mediated inhibitory action of adenosine on mast cell degranulation has also been reported (16). and the objective of this research nas to investigate the role of adenosine A(2) receptors in modulating inosine-induced mast cell degranulation and subsequent vasoconstriction of microvessels. Methods: Cheek pouches of the Golden hamster were prepared for in vivo microscopy. Adenosine, inosine, and other agents were applied either globally in the superfusion solution or to selected regions of the tissue by pipette Results: Micropipette application of 10(-4) M inosine to periarteriolar mast cells caused a vasoconstriction and an associated mast cell degranulation in 71% of the arterioles tested. The average diameter reduction was 29 +/- 5%. To establish a modulatory role for the A(2) receptor, low doses of adenosine (100 nM and 10 nM) were applied globally via the superfusion prior to inosine stimulation. This adenosine pretreatment resulted in a decrease in the incidence of the inosine-induced vasoconstriction (17% and 31%), as well as smaller constrictions (0.5 +/- 1% and 7 +/- 3%). Mast cell degranulation was also reduced by; pretreatment with adenosine. as evidenced by a decreased number of mast cells exhibiting ruthenium red dye uptake. The inhibitory effect of adenosine could be eliminated by pretreatment with the nonselective A(1)/A(2) antagonist 8-(p-sulfophenyl) theophylline, which restored the inosine-induced responses to control values. To demonstrate that the effect was A(2 alpha)-mediated. vessels were pretreated with the selective A(2 alpha) agonist 2-[4-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Following this treatment: constriction in response to microapplication of inosine (10(-4) M) occurred in only 11% of the vessels tested, the average constriction was reduced to 2 +/- 2% and no mast cell de granulation was observed. Conclusions: We conclude that mast cell degranulation carl be inhibited iia activation of an adenosine A(2 alpha) receptor; which activation occurs at a lower concentration of adenosine than stimulatory A(3), receptor activation. This finding may have implications for the pathology of ischemia.