Document Detail

Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists upon chronic administration.
MedLine Citation:
PMID:  8229754     Owner:  NLM     Status:  MEDLINE    
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)
R L Webb; M A Sills; J P Chovan; J V Peppard; J E Francis
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  267     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1993 Oct 
Date Detail:
Created Date:  1993-11-29     Completed Date:  1993-11-29     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  287-95     Citation Subset:  IM    
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey.
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MeSH Terms
Adenosine / analogs & derivatives*,  blood,  metabolism,  pharmacology
Antihypertensive Agents / administration & dosage*
Blood Pressure / drug effects
Corpus Striatum / metabolism
Cyclohexanes / blood,  pharmacology*
Dose-Response Relationship, Drug
Drug Tolerance
Heart Rate / drug effects
Phenethylamines / blood,  metabolism,  pharmacology
Rats, Inbred SHR
Receptors, Purinergic P1 / drug effects*
Renin / blood
Time Factors
Reg. No./Substance:
0/Antihypertensive Agents; 0/Cyclohexanes; 0/Phenethylamines; 0/Receptors, Purinergic P1; 120225-54-9/CGS 21680; 124498-52-8/2-((2-cyclohexylethyl)amino)adenosine; 124498-87-9/2-((2-(1-cyclohexen-1-yl)ethyl)amino)adenosine; 58-61-7/Adenosine; EC

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