DEVELOPMENT OF TOLERANCE TO THE ANTIHYPERTENSIVE EFFECTS OF HIGHLY SELECTIVE ADENOSINE-A(2A) AGONISTS UPON CHRONIC ADMINISTRATION

Three highly A2a-selective adenosine agonists were examined for their effects on blood pressure during chronic administration in conscious s pontaneously hypertensive rats. Sodium ethyl-beta-D-ribofuranuronamido syl)-9H-purin-2-yl] amino]ethyl]benzenepropionate (CGS 21680C) 2-[(2-c yclohexyl-. ethyl)amino]adenosine (CGS 22492) and 2-[[2-(1-cyclohexen- 1-. yl)ethyl]amino]adenosine (CGS 22989) were administered at a rate o f 0.25 and 0.5 mug/kg/min i.v. for 2 weeks using osmotic minipumps. Si gnificant systolic blood pressure reductions were seen in the A2a agon ist-treated groups compared to vehicle-treated (50% dimethyl sulfoxide ) animals. Maximum effects occurred on days 1 and 2 in the treated ani mals. However, the antihypertensive effect diminished with time such t hat no differences between treatments were seen at 2 weeks. In contras t, a sustained antihypertensive effect was evident with benazeprilat ( an angiotensin converting enzyme inhibitor). Tolerance was associated with a decrease in B(max) values (375 +/- 22, 410 +/- 18 and 548 +/- 1 7 fmol/mg of protein in the CGS 21680C, CGS 22989- and vehicle-treated spontaneously hypertensive rats, respectively) without affecting the K(d) value. In addition to a reduction in A2 receptor number, increase d heart rates were seen on day 1 and 2 in both the CGS 21680C- and CGS 22989-treated animals and a mild stimulation of the renin angiotensin system occurred with CGS 21680C. In separate acute experiments using identical infusion rates, plasma concentrations of CGS 21680C were 157 +/- 41 ng/ml compared to 30.4 +/- 8.8 ng/ml after chronic administrat ion. These studies demonstrate that chronic administration of two high ly A2a-selective adenosine agonists resulted in tolerance to their ant ihypertensive actions with a down-regulation of the adenosine A2a rece ptor. In addition, other factors likely contributed to the development of tolerance including enhanced clearance of drug and stimulation of compensatory systems such as the renin angiotensin system and activati on of neural reflexes.