Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists upon chronic administration.
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)
Webb
R L
RL
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey.
Sills
M A
MA
Chovan
J P
JP
Peppard
J V
JV
Francis
J E
JE
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D003510:Cyclohexanes / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010627:Phenethylamines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D012083:Renin / Q000097:blood; D013997:Time Factors
D000959:Antihypertensive Agents; D003510:Cyclohexanes; D010627:Phenethylamines; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C070485:2-((2-cyclohexylethyl)amino)adenosine; C083894:2-((2-(1-cyclohexen-1-yl)ethyl)amino)adenosine; D012083:Renin; D000241:Adenosine