title: Elevated afterload, neuroendocrine stimulation, and human heart failure increase BNP levels and inhibit preload-dependent SERCA upregulation.
abstract: BACKGROUND
  In heart failure, brain-type natriuretic peptide (BNP) is elevated and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) downregulated. We previously showed that preload-induced SERCA-upregulation is suppressed by exogenous BNP.
  
  
  RESULTS
  Here we tested the hypothesis that afterload and neurohumoral activation would counterregulate preload-dependent SERCA upregulation through BNP, which finally results in decreased SERCA levels. We studied the effects of 6 hours preload, afterload, and isoproterenol stimulation on BNP and SERCA mRNA expression in rabbit and human failing muscles strips. Preload resulted in a pronounced upregulation of SERCA by 149% (isotonic versus slack, P<0.01). This upregulation was largely suppressed in afterloaded muscles (isometric versus slack: +32%; P<0.05). Similarly, presence of isoproterenol prevented SERCA upregulation in isotonic muscles. Afterload and isoproterenol resulted in a pronounced increase in BNP expression compared with slack by 225% (P<0.05) and 198% (P<0.01), respectively. Isoproterenol also increased expression of phospholamban by 84% (P<0.01). SERCA upregulation in preloaded muscles is associated with frequency-dependent potentiation of contractile force, which is absent in afterloaded muscles. In failing human myocardium, BNP expression was upregulated compared with nonfailing (+631%; P<0.05). Neither unloading nor preload or afterload induced a change in SERCA or BNP expression after 6 hours.
  
  
  CONCLUSIONS
  Afterload and neuroendocrine stimulation increase BNP expression thereby causing inhibition of preload-dependent SERCA upregulation. In failing human myocardium, high BNP expression may underlie the loss of preload-dependent upregulation of SERCA. BNP may thus contribute to adverse myocardial remodelling in heart failure.
authors.affiliation: Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Robert-Koch-Strasse 40, Göttingen, Germany. ktoischer@med.uni-goettingen.de
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Harald
authors.initials: H
authors.lastname: Kögler
authors.forename: Gero
authors.initials: G
authors.lastname: Tenderich
authors.forename: Cornelia
authors.initials: C
authors.lastname: Grebe
authors.forename: Tim
authors.initials: T
authors.lastname: Seidler
authors.forename: Phuc Nguyen
authors.initials: PN
authors.lastname: Van
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Reiner
authors.initials: R
authors.lastname: Körfer
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D009490:Neurosecretory Systems / Q000187:drug effects / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D015854:Up-Regulation / Q000187:drug effects*; D055815:Young Adult; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D007545:Isoproterenol; D020097:Natriuretic Peptide, Brain; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban