Endothelin-A receptor antagonism modifies cardiovascular risk factors in CKD

J Am Soc Nephrol. 2013 Jan;24(1):31-6. doi: 10.1681/ASN.2012040355. Epub 2012 Dec 14.


Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.

Trial registration: ClinicalTrials.gov NCT00810732.

Publication types

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

MeSH terms

  • Adult
  • Biomarkers / blood
  • Biomarkers / urine
  • Blood Pressure / drug effects
  • Cardiovascular Diseases / prevention & control*
  • Cross-Over Studies
  • Double-Blind Method
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / blood
  • Endothelin-1 / urine
  • Female
  • Humans
  • Isoxazoles / pharmacology
  • Isoxazoles / therapeutic use*
  • Male
  • Middle Aged
  • Nifedipine / therapeutic use
  • Proteinuria / drug therapy
  • Pulse Wave Analysis
  • Renal Insufficiency, Chronic / complications*
  • Renal Insufficiency, Chronic / drug therapy
  • Renal Insufficiency, Chronic / metabolism
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use*
  • Vascular Stiffness / drug effects
  • Vasodilator Agents / therapeutic use


  • Biomarkers
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Isoxazoles
  • Thiophenes
  • Vasodilator Agents
  • Nifedipine
  • sitaxsentan

Associated data

  • ClinicalTrials.gov/NCT00810732