Document Detail

Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice.
MedLine Citation:
PMID:  10217548     Owner:  NLM     Status:  MEDLINE    
1. We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor mice. The in vitro pharmacology of these agonists was determined at recombinant (human) alpha2-adrenoceptors and at endogenous (dog) alpha2A-adrenoceptors. 2. In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 microg kg(-1), i.v.) and clonidine (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased blood pressure and heart rate. 3. In D79N alpha2A-adrenoceptor mice, responses to rilmenidine and moxonidine did not differ from vehicle control. Clonidine-induced hypotension was absent, but dose-dependent hypertension and bradycardia were observed. 4. In wild-type mice, responses to moxonidine (1 mg kg(-1), i.v.) were antagonized by the non-selective, non-imidazoline alpha2-adrenoceptor antagonist, RS-79948-197 (1 mg kg(-1), i.v.). 5. Affinity estimates (pKi) at human alpha2A-, alpha2B- and alpha2C-adrenoceptors, respectively, were: rilmenidine (5.80, 5.76 and 5.33), moxonidine (5.37, <5 and <5) and clonidine (7.21, 7.16 and 6.87). In a [35S]-GTPgammaS incorporation assay, moxonidine and clonidine were alpha2A-adrenoceptor agonists (pEC50/intrinsic activity relative to noradrenaline): moxonidine (5.74/0.85) and clonidine (7.57/0.32). 6. In dog saphenous vein, concentration-dependent contractions were observed (pEC50/intrinsic activity relative to noradrenaline): rilmenidine (5.83/0.70), moxonidine (6.48/0.98) and clonidine (7.22/0.83). Agonist-independent affinities were obtained with RS-79948-197. 7. Thus, expression of alpha2A-adrenoceptors is a prerequisite for the cardiovascular effects of moxonidine and rilmenidine in conscious mice. There was no evidence of I1-imidazoline receptor-mediated effects. The ability of these compounds to act as alpha2A-adrenoceptor agonists in vitro supports this conclusion.
Q M Zhu; J D Lesnick; J R Jasper; S J MacLennan; M P Dillon; R M Eglen; D R Blue
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  British journal of pharmacology     Volume:  126     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  1999 Mar 
Date Detail:
Created Date:  1999-06-22     Completed Date:  1999-06-22     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1522-30     Citation Subset:  IM    
Center for Biological Research, Neurobiology Unit, Roche Bioscience, Palo Alto, California 94304, USA.
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MeSH Terms
Adrenergic alpha-Antagonists / metabolism,  pharmacology
Amino Acid Substitution
Binding, Competitive / drug effects
Blood Pressure / drug effects
Cardiovascular Agents / metabolism,  pharmacology*
Cell Line
Clonidine / metabolism,  pharmacology
Heart Rate / drug effects
Imidazoles / metabolism,  pharmacology
Isoquinolines / metabolism,  pharmacology
Mice, Inbred Strains
Mice, Transgenic
Naphthyridines / metabolism,  pharmacology
Oxazoles / metabolism,  pharmacology
Quinolizines / diagnostic use
Radioligand Assay
Receptors, Adrenergic, alpha-2 / drug effects*,  genetics,  metabolism
Recombinant Fusion Proteins / genetics,  metabolism
Saphenous Vein / drug effects,  metabolism
Tritium / diagnostic use
Reg. No./Substance:
0/ADRA2A protein, human; 0/Adra2a protein, mouse; 0/Adrenergic alpha-Antagonists; 0/Cardiovascular Agents; 0/Imidazoles; 0/Isoquinolines; 0/Naphthyridines; 0/Oxazoles; 0/Quinolizines; 0/RS 79948-197; 0/Receptors, Adrenergic, alpha-2; 0/Recombinant Fusion Proteins; 10028-17-8/Tritium; 111466-41-2/L 657743; 4205-90-7/Clonidine; 54187-04-1/rilmenidine; 75438-57-2/moxonidine

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