PT  - JOURNAL ARTICLE
AU  - R L Webb
AU  - M A Sills
AU  - J P Chovan
AU  - J V Peppard
AU  - J E Francis
TI  - Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists upon chronic administration.
DP  - 1993 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 287--295
VI  - 267
IP  - 1
4099  - http://jpet.aspetjournals.org/content/267/1/287.short
4100  - http://jpet.aspetjournals.org/content/267/1/287.full
SO  - J Pharmacol Exp Ther1993 Oct 01; 267
AB  - Three highly A2a-selective adenosine agonists were examined for their effects on blood pressure during chronic administration in conscious spontaneously hypertensive rats. Sodium 4-[2-[[6-amino-9-(N-ethyl-beta-D-ribofuranuronamidosyl)-9H-purin-2 -yl] amino]ethyl]benzenepropionate (CGS 21680C) 2-[(2-cyclohexyl-ethyl)amino]adenosine (CGS 22492) and 2-[[2-(1-cyclohexen-1-yl)ethyl]amino]adenosine (CGS 22989) were administered at a rate of 0.25 and 0.5 micrograms/kg/min i.v. for 2 weeks using osmotic minipumps. Significant systolic blood pressure reductions were seen in the A2a agonist-treated groups compared to vehicle-treated (50% dimethyl sulfoxide) animals. Maximum effects occurred on days 1 and 2 in the treated animals. However, the antihypertensive effect diminished with time such that no differences between treatments were seen at 2 weeks. In contrast, a sustained antihypertensive effect was evident with benazeprilat (an angiotensin converting enzyme inhibitor). Tolerance was associated with a decrease in Bmax values (375 +/- 22, 410 +/- 18 and 548 +/- 17 fmol/mg of protein in the CGS 21680C, CGS 22989- and vehicle-treated spontaneously hypertensive rats, respectively) without affecting the Kd value. In addition to a reduction in A2 receptor number, increased 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 administration.(ABSTRACT TRUNCATED AT 250 WORDS)