title: The positive inotropic effect of relaxin-2 in human atrial myocardium is preserved in end-stage heart failure: role of G(i)-phosphoinositide-3 kinase signaling.
abstract: BACKGROUND
  Relaxin-2, a candidate drug for acute heart failure, has been tested successfully in the first human trials. We investigated relaxin's inotropic effects in human myocardium.
  
  
  RESULTS
  In atrial samples from donor (n = 7) and failing (n = 7) hearts, relaxin-2 evoked remarkable positive inotropic effects: showing a half maximum effective concentration of < 1 nmol/L, the maximum peak developed tension (PDT) rose to approximately 270% of baseline, without differences between failing and nonfailing myocardium. The effects critically depended on protein kinase A activation and inhibition of the transient potassium outward current; phosphoinositide-3 kinase inhibition and pertussis toxin pretreatment moderately blunted the effects in nonfailing but markedly suppressed them in failing myocardium. Action potential recordings revealed identical effects of inhibition of the transient potassium outward current and relaxin. In ventricular myocardium, however, relaxin did not show any inotropic effects. The expression of the RXFP1 receptor was moderately decreased in failing compared with nonfailing atrial myocardium but not detectable in any ventricular samples.
  
  
  CONCLUSIONS
  Relaxin is a positive inotrope in nonfailing and failing human atria, with critical involvement of protein kinase A and inhibition of the transient potassium outward current and an increasing role for G(i) protein-phosphoinositide-3 kinase signaling in failing myocardium.
authors.affiliation: Department of Cardiology and Angiology, Charité-University Medicine Berlin, Campus Mitte, Schumannstrasse 20/21, Berlin, Germany. thomas.dschietzig@charite.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Dschietzig
authors.forename: Konstantin
authors.initials: K
authors.lastname: Alexiou
authors.forename: Hans-Tilman
authors.initials: HT
authors.lastname: Kinkel
authors.forename: Gert
authors.initials: G
authors.lastname: Baumann
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
authors.forename: Karl
authors.initials: K
authors.lastname: Stangl
mesh_terms: D000200:Action Potentials; D000328:Adult; D000704:Analysis of Variance; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000187:drug effects*; D005260:Female; D006325:Heart Atria / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy*; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D010716:Phosphatidylinositols; D012065:Relaxin / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D010716:Phosphatidylinositols; C095068:RLN2 protein, human; D012065:Relaxin; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human