Activation of adenosine A(2 alpha) receptors inhibits mast cell degranulation and mast cell-dependent vasoconstriction

Objective: Adenosine and inosine accumulate in tissue during periods of isc hemia and both molecules have been shown to degranulate mast cells in the h amster cheek; pouch via activation of an A(3) receptor. An A(2)-mediated in hibitory action of adenosine on mast cell degranulation has also been repor ted (16). and the objective of this research nas to investigate the role of adenosine A(2) receptors in modulating inosine-induced mast cell degranula tion and subsequent vasoconstriction of microvessels. Methods: Cheek pouches of the Golden hamster were prepared for in vivo micr oscopy. Adenosine, inosine, and other agents were applied either globally i n the superfusion solution or to selected regions of the tissue by pipette Results: Micropipette application of 10(-4) M inosine to periarteriolar mas t 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 ade nosine (100 nM and 10 nM) were applied globally via the superfusion prior t o inosine stimulation. This adenosine pretreatment resulted in a decrease i n the incidence of the inosine-induced vasoconstriction (17% and 31%), as w ell as smaller constrictions (0.5 +/- 1% and 7 +/- 3%). Mast cell degranula tion was also reduced by; pretreatment with adenosine. as evidenced by a de creased number of mast cells exhibiting ruthenium red dye uptake. The inhib itory effect of adenosine could be eliminated by pretreatment with the nons elective A(1)/A(2) antagonist 8-(p-sulfophenyl) theophylline, which restore d 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-ethylcarboxam idoadenosine (CGS21680). Following this treatment: constriction in response to microapplication of inosine (10(-4) M) occurred in only 11% of the vess els tested, the average constriction was reduced to 2 +/- 2% and no mast ce ll 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 activat ion. This finding may have implications for the pathology of ischemia.