1. The adenosine A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA) induces hypotension in the anaesthetized rat. The present experiments were carried out to explore the role of mast cells in the response. 2. Intravenous injection of APNEA (1-30 micrograms kg-1 to rats in which the A3 receptor-mediated response had been isolated by pretreatment with 8-(p-sulphophenyl) theophylline (8-SPT)), induced dose-related falls in blood pressure accompanied at higher doses by small falls in heart rate. Responses to the mast cell degranulating agent, compound 48/80 (10-300 micrograms kg-1, i.v.) were qualitatively similar to those to APNEA. 3. Pretreatment with sodium cromoglycate (0.25-20 mg kg-1, i.v.) induced dose-related, although incomplete, blockade of the hypotensive responses to APNEA. At 20 mg kg-1, sodium cromoglycate also inhibited the cardiovascular response to compound 48/80 but had no effects on those to the selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) or the selective A2A receptor agonist, 2-[p-(2-carboxyethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680). Lodoxamide (0.01-20 mg kg-1) also blocked selectively but incompletely the response to APNEA. 4. The cardiovascular responses to compound 48/80 (10-300 micrograms kg-1, i.v.) were markedly suppressed in animals which had received repeated doses of the compound by the intraperitoneal route. Similarly APNEA was essentially devoid of cardiovascular activity in such preparations. In contrast, responses to CPA were similar in animals treated repeatedly with compound 48/80 to those obtained in control animals. 5. Plasma and serum histamine concentrations were markedly increased associated with the pronounced hypotensive responses induced by intravenous injections of APNEA (30 or 100 microg kg-1) in the presence of 8-SPT, or compound 48/80 (300 microg kg-1).6. Taken together the data implicate the mast cell in a key role in adenosine A3 receptor-mediated hypotension in the anaesthetized rat.