title: Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators.
abstract: OBJECTIVE
  To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF).
  
  
  BACKGROUND
  Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest.
  
  
  METHODS
  The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%.
  
  
  RESULTS
  Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant.
  
  
  CONCLUSIONS
  In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.
authors.affiliation: Division of Cardiology, University Hospital, Zürich, Switzerland.
authors.forename: L E
authors.initials: LE
authors.lastname: Spieker
authors.forename: V
authors.initials: V
authors.lastname: Mitrovic
authors.forename: G
authors.initials: G
authors.lastname: Noll
authors.forename: R
authors.initials: R
authors.lastname: Pacher
authors.forename: M R
authors.initials: MR
authors.lastname: Schulze
authors.forename: J
authors.initials: J
authors.lastname: Muntwyler
authors.forename: C
authors.initials: C
authors.lastname: Schalcher
authors.forename: W
authors.initials: W
authors.lastname: Kiowski
authors.forename: T F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D002395:Catecholamines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D002395:Catecholamines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan