Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease

Hypertension. 2011 Apr;57(4):772-9. doi: 10.1161/HYPERTENSIONAHA.110.167486. Epub 2011 Feb 28.


Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (-0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.

Trial registration: NCT00810732.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antihypertensive Agents / therapeutic use
  • Arteries / drug effects
  • Blood Pressure / drug effects*
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Therapy, Combination
  • Endothelin A Receptor Antagonists*
  • Female
  • Glomerular Filtration Rate / drug effects
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / etiology
  • Isoxazoles / blood
  • Isoxazoles / therapeutic use*
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / drug therapy*
  • Male
  • Middle Aged
  • Nifedipine / therapeutic use
  • Proteinuria / drug therapy*
  • Proteinuria / etiology
  • Radioimmunoassay
  • Thiophenes / blood
  • Thiophenes / therapeutic use*
  • Treatment Outcome
  • Vascular Resistance / drug effects
  • Vasodilator Agents / therapeutic use


  • Antihypertensive Agents
  • Endothelin A Receptor Antagonists
  • Isoxazoles
  • Thiophenes
  • Vasodilator Agents
  • Nifedipine
  • sitaxsentan

Associated data