Document Detail


Myocardial beta-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity.
MedLine Citation:
PMID:  10611414     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic administration of norepinephrine for 8 weeks has been shown to reduce neuronal norepinephrine uptake activity and increase interstitial norepinephrine concentration in the heart. To determine whether the changes could lead to myocardial beta-adrenoceptor down-regulation or beta-adrenergic subsensitivity, we measured left ventricular contractile responses to dobutamine, myocardial beta-adrenoceptor density, beta subtype distribution, competitive inhibition agonist binding, and adenylyl cyclase activity activation by isoproterenol, 5'-guanylylimidodiphosphate, and forskolin in dogs after a norepinephrine or saline infusion for 8 weeks. We found that norepinephrine infusion reduced myocardial beta-adrenoceptor density, beta(1)-adrenoceptor subtype density, and high-affinity site for isoproterenol. Left ventricular contractile responses to dobutamine were reduced in the norepinephrine-infused animals. In addition, norepinephrine infusion decreased the basal adenylyl cyclase activity and the adenylyl cyclase responses to isoproterenol, 5'-guanylylimidodiphosphate, and forskolin. The findings indicate that a decrease in cardiac norepinephrine uptake predisposes the heart to norepinephrine-induced myocardial beta-adrenoceptor down-regulation, and that norepinephrine, when present in a sufficient amount over a long period as it is in chronic heart failure, can reduce myocardial beta-adrenergic responsiveness by both homologous and heterologous desensitization.
Authors:
E Dong; A Yatani; A Mohan; C S Liang
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  European journal of pharmacology     Volume:  384     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  1999 Nov 
Date Detail:
Created Date:  2000-01-18     Completed Date:  2000-01-18     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  17-24     Citation Subset:  IM    
Affiliation:
Cardiology Unit, Box 679, Cardiology Research Laboratories, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenylate Cyclase / metabolism
Adrenergic beta-Agonists / pharmacology
Adrenergic beta-Antagonists / metabolism,  pharmacology
Animals
Binding, Competitive / drug effects
Dobutamine / pharmacology
Dogs
Down-Regulation / drug effects
Enzyme Activation / drug effects
Forskolin / pharmacology
Guanylyl Imidodiphosphate / pharmacology
Heart Ventricles / drug effects*,  metabolism
Hemodynamics / drug effects
Imidazoles / pharmacology
Iodine Radioisotopes / diagnostic use
Iodocyanopindolol / metabolism,  pharmacology
Isoproterenol / pharmacology
Myocardial Contraction / drug effects
Norepinephrine / pharmacokinetics*,  pharmacology*
Receptors, Adrenergic, beta / drug effects,  metabolism*
Receptors, Adrenergic, beta-1 / metabolism
Receptors, Adrenergic, beta-2 / metabolism
Ventricular Function
Grant Support
ID/Acronym/Agency:
HL-39260/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Adrenergic beta-Antagonists; 0/Imidazoles; 0/Iodine Radioisotopes; 0/Receptors, Adrenergic, beta; 0/Receptors, Adrenergic, beta-1; 0/Receptors, Adrenergic, beta-2; 34273-04-6/Guanylyl Imidodiphosphate; 34368-04-2/Dobutamine; 51-41-2/Norepinephrine; 66428-89-5/Forskolin; 7683-59-2/Isoproterenol; 81015-67-0/CGP 20712A; 83498-72-0/Iodocyanopindolol; EC 4.6.1.1/Adenylate Cyclase

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


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