Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators

J Am Coll Cardiol. 2000 Jun;35(7):1745-52. doi: 10.1016/s0735-1097(00)00649-5.

Abstract

Objectives: 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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catecholamines / blood
  • Dose-Response Relationship, Drug
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / blood
  • Female
  • Heart Failure / blood
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Middle Aged
  • Phenylpropionates / therapeutic use*
  • Pyrimidines / therapeutic use*

Substances

  • Catecholamines
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Phenylpropionates
  • Pyrimidines
  • darusentan