Document Detail

Bucindolol exerts agonistic activity on the propranolol-insensitive state of beta1-adrenoceptors in human myocardium.
MedLine Citation:
PMID:  11861783     Owner:  NLM     Status:  MEDLINE    
In congestive heart failure patients, treatment with beta-adrenoceptor antagonists improves symptoms and decreases mortality. However, intrinsic sympathomimetic activity of beta-adrenoceptor antagonists might be disadvantageous in chronic heart failure. The nonselective beta1- and beta2-adrenoceptor antagonist bucindolol has failed to decrease mortality in clinical trials. A putative beta4-adrenoceptor, which mediates positive inotropic effects by activation of the adenylate cyclase has been described. Recently, this putative beta4-adrenoceptor has been identified to be a propranolol-insensitive state of the beta1-adrenoceptor. The present study aimed to characterize whether bucindolol exhibits agonistic activity on this atypical beta1-adrenoceptor state as one possible reason for clinical inefficiency. For comparison (S)-4-(3'-t-butylamino-1'-hydroxypropoxy)-benzimidozole-2 (CGP 12177), metoprolol, and nebivolol were investigated. Bucindolol did not reveal intrinsic sympathomimetic activity in electrically driven (1 Hz, 37 degrees C), forskolin-stimulated, left ventricular papillary muscle strips (donor hearts, nonfailing; n = 5) and in right auricular trabeculae (bypass operation; n = 4). Functional studies on the propranolol-insensitive state of beta1-adrenoceptors were performed in isolated muscle preparations after beta1- and beta2-adrenoceptor antagonism (propranolol, 1 microM), inhibition of beta3-mediated inotropic effects (N-nitro-L-arginine, 100 microM) and forskolin treatment (0.3 microM). Positive inotropic response to stimulation of atypical state beta1-adrenoceptors could be demonstrated in right auricular as well as left ventricular human myocardium (CGP 12177 treatment, 10 microM). Under these conditions, also bucindolol, but not metoprolol and nebivolol, significantly increased contractility (all 10 microM). In conclusion, bucindolol but not metoprolol or nebivolol mediate positive inotropic effects in human myocardium due to activation of atypical state beta1-adrenoceptors. Thus, the agonistic activity of bucindolol may influence outcome in heart failure patients.
Andreas Bundkirchen; Klara Brixius; Birgit Bölck; Robert H G Schwinger
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  300     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-02-25     Completed Date:  2002-03-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  794-801     Citation Subset:  IM    
Labor für Herzmuskelphysiologie und Molekulare Kardiologie, Klinik III für Innere Medizin der Universität zu Köln, Köln, Germany.
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MeSH Terms
Adrenergic beta-Agonists / pharmacology*
Adrenergic beta-Antagonists / pharmacology*
Atrial Function, Right / drug effects
Benzopyrans / pharmacology
Ethanolamines / pharmacology
Heart / drug effects*
Metoprolol / pharmacology
Middle Aged
Myocardial Contraction / drug effects
Myocardium / metabolism*
Papillary Muscles / drug effects
Propanolamines / pharmacology*
Propranolol / pharmacology*
Receptors, Adrenergic, beta-1 / drug effects*
Ventricular Function, Left / drug effects
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Adrenergic beta-Antagonists; 0/Benzopyrans; 0/Ethanolamines; 0/Propanolamines; 0/Receptors, Adrenergic, beta-1; 37350-58-6/Metoprolol; 525-66-6/Propranolol; 70369-47-0/bucindolol; 81047-99-6/CGP 12177; 99200-09-6/nebivolol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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