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Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists upon chronic administration

RL Webb, MA Sills, JP Chovan, JV Peppard and JE Francis

Research Department, CIBA-GEIGY Corporation, Summit, New Jersey.

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)

Volume 267, Issue 1, pp. 287-295, 10/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics.