title: Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.
abstract: BACKGROUND
  Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy.
  
  
  RESULTS
  This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index </=2.5 L. min(-1). m(-2) were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure (P</=0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan.
  
  
  CONCLUSIONS
  In patients with moderate to severe heart failure receiving conventional therapy, acute ET(A) receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.
authors.affiliation: Cardiomyopathy Program and Cardiovascular Section, Boston University Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Givertz
authors.forename: W S
authors.initials: WS
authors.lastname: Colucci
authors.forename: T H
authors.initials: TH
authors.lastname: LeJemtel
authors.forename: S S
authors.initials: SS
authors.lastname: Gottlieb
authors.forename: J M
authors.initials: JM
authors.lastname: Hare
authors.forename: M T
authors.initials: MT
authors.lastname: Slawsky
authors.forename: C V
authors.initials: CV
authors.lastname: Leier
authors.forename: E
authors.initials: E
authors.lastname: Loh
authors.forename: J M
authors.initials: JM
authors.lastname: Nicklas
authors.forename: B E
authors.initials: BE
authors.lastname: Lewis
mesh_terms: D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000503:physiopathology*; D002908:Chronic Disease; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D011652:Pulmonary Circulation / Q000187:drug effects*; D044022:Receptor, Endothelin A; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014664:Vasodilation; D014665:Vasodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009638:Norepinephrine