Vol. 302, Issue 2, 725-730, August 2002

Suppression of Adenosine A₃ Receptor-Mediated Hypotension and Mast Cell Degranulation in the Rat by Dexamethasone

Jason P. Hannon, Bruno Tigani, Henk-Jan Schuurman and John R. Fozard

Research Department, Novartis Pharma AG, Basel, Switzerland

Dexamethasone increases the expression of adenosine A₃ receptors and augments degranulation in response to their activation in the rat basophilic leukemia cell line, RBL-2H3. We have studied the effects of dexamethasone on mast cell activation induced by A₃ receptor stimulation in vivo. Administration of the A₃ receptor agonist APNEA [N⁶-2-(4 aminophenyl)ethyladenosine; 10-30 µg kg¹ i.v.] to anesthetized Sprague-Dawley rats induced falls in blood pressure. Pretreatment with dexamethasone (1 mg kg¹, i.p., 24 h) blocked the hypotensive response to APNEA but not those induced by the A₁ receptor agonist N⁶-cyclopentyladenosine, the A_2A receptor agonist 2-[p-(2-carboxyethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine, or the mast cell degranulating agent compound 48/80 (100-300 µg kg¹, i.v.). APNEA (10 and 30 µg kg¹, i.v.) and compound 48/80 (100 and 300 µg kg¹, i.v.) increased plasma histamine concentrations dose dependently. Pretreatment with dexamethasone significantly inhibited the increases induced by the lower doses of each compound. APNEA induced degranulation of mast cells in thymus but not in skin or skeletal muscle, whereas compound 48/80 induced degranulation in each tissue. Pretreatment with dexamethasone inhibited APNEA-induced degranulation of mast cells in the thymus and slightly, yet significantly, reduced degranulation induced by compound 48/80. Thus, in contrast to the findings in RBL-2H3 cells in vitro, in the whole animal, dexamethasone down-regulates the response of the mast cell to A₃ receptor activation. The qualitatively similar effects on compound 48/80 suggest that dexamethasone suppresses mast cell responsiveness by modulating site(s) downstream from the adenosine A₃ receptor, possibly at the level of the G_i family of trimeric GTP-binding proteins.