title: Evidence for reduction of norepinephrine uptake sites in the failing human heart.
abstract: OBJECTIVE
  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.affiliation: Klinik III für Innere Medizin, Universität zu Köln, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: K
authors.initials: K
authors.lastname: La Rosée
authors.forename: R H
authors.initials: RH
authors.lastname: Schwinger
authors.forename: E
authors.initials: E
authors.lastname: Erdmann
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D016027:Heart Transplantation; D006350:Heart Valve Prosthesis; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D011941:Receptors, Adrenergic / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011941:Receptors, Adrenergic; D009638:Norepinephrine