Document Detail


Evidence for reduction of norepinephrine uptake sites in the failing human heart.
MedLine Citation:
PMID:  7798493     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND: Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS: The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS: The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.
Authors:
M B?hm; K La Ros?e; R H Schwinger; E Erdmann
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  25     ISSN:  0735-1097     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  1995 Jan 
Date Detail:
Created Date:  1995-01-25     Completed Date:  1995-01-25     Revised Date:  2010-03-24    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  146-53     Citation Subset:  AIM; IM    
Affiliation:
Klinik III f?r Innere Medizin, Universit?t zu K?ln, Germany.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Dose-Response Relationship, Drug
Drug Interactions
Female
Heart Failure / metabolism*
Heart Transplantation
Heart Valve Prosthesis
Humans
Male
Middle Aged
Mitral Valve
Myocardial Contraction / drug effects
Myocardium / chemistry,  cytology,  metabolism*
Neurons / chemistry,  drug effects,  metabolism
Norepinephrine / analysis,  metabolism*,  pharmacology
Radioligand Assay
Receptors, Adrenergic / analysis,  drug effects,  metabolism*
Chemical
Reg. No./Substance:
0/Receptors, Adrenergic; 51-41-2/Norepinephrine

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