Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure

Michael M. Givertz, Wilson S. Colucci, Thierry H. LeJemtel, Stephen S. Gottlieb, Joshua M. Hare, Mara T. Slawsky, Carl V. Leier, Evan Loh, John M. Nicklas, Bruce E. Lewis

Research output: Contribution to journalArticle

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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)2922-2927
Number of pages6
JournalCirculation
Volume101
Issue number25
StatePublished - Jun 27 2000

Fingerprint

Endothelin A Receptors
Vasodilation
Heart Failure
Lung
Endothelin-1
Vascular Resistance
Pulmonary Artery
Pulmonary Wedge Pressure
Hemodynamics
Placebos
Pressure
Atrial Pressure
Vascular Smooth Muscle
Angiotensin-Converting Enzyme Inhibitors
Diuretics
Pulmonary Hypertension
Intravenous Infusions
Catheterization
Stroke Volume
Hypertrophy

Keywords

  • Endothelin
  • Heart failure
  • Hemodynamics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Givertz, M. M., Colucci, W. S., LeJemtel, T. H., Gottlieb, S. S., Hare, J. M., Slawsky, M. T., ... Lewis, B. E. (2000). Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation, 101(25), 2922-2927.

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. / Givertz, Michael M.; Colucci, Wilson S.; LeJemtel, Thierry H.; Gottlieb, Stephen S.; Hare, Joshua M.; Slawsky, Mara T.; Leier, Carl V.; Loh, Evan; Nicklas, John M.; Lewis, Bruce E.

In: Circulation, Vol. 101, No. 25, 27.06.2000, p. 2922-2927.

Research output: Contribution to journalArticle

Givertz, MM, Colucci, WS, LeJemtel, TH, Gottlieb, SS, Hare, JM, Slawsky, MT, Leier, CV, Loh, E, Nicklas, JM & Lewis, BE 2000, 'Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure', Circulation, vol. 101, no. 25, pp. 2922-2927.
Givertz MM, Colucci WS, LeJemtel TH, Gottlieb SS, Hare JM, Slawsky MT et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation. 2000 Jun 27;101(25):2922-2927.
Givertz, Michael M. ; Colucci, Wilson S. ; LeJemtel, Thierry H. ; Gottlieb, Stephen S. ; Hare, Joshua M. ; Slawsky, Mara T. ; Leier, Carl V. ; Loh, Evan ; Nicklas, John M. ; Lewis, Bruce E. / Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. In: Circulation. 2000 ; Vol. 101, No. 25. pp. 2922-2927.
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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. Methods and 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.",
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AU - Givertz, Michael M.

AU - Colucci, Wilson S.

AU - LeJemtel, Thierry H.

AU - Gottlieb, Stephen S.

AU - Hare, Joshua M.

AU - Slawsky, Mara T.

AU - Leier, Carl V.

AU - Loh, Evan

AU - Nicklas, John M.

AU - Lewis, Bruce E.

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N2 - 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. Methods and 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.

AB - 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. Methods and 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.

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