title: Chronic blockade of endothelin A and B receptors using macitentan in experimental renovascular disease.
abstract: BACKGROUND
  Emerging research has identified the endothelin (ET)-1 pathway as a potential target for novel renoprotective therapies. We recently showed that selective ET-A receptor antagonism in chronic renovascular disease (RVD) improves renal function and reduces renal injury. Although ET-A and -B have opposing roles, in some clinical situations they may induce similar effects. Thus, we hypothesized that simultaneous blockade of the ET-A and -B receptors would protect the kidney during RVD.
  
  
  METHODS
  Unilateral RVD was induced in pigs. After 6 weeks, single-kidney function was quantified in vivo using multi-detector computer tomography. Pigs were subsequently divided into untreated (RVD, n = 7) or daily-treated with the dual ET-A/B receptor antagonist macitentan (RVD + macitentan, n = 6) for 4 weeks. At 10 weeks, in vivo studies were repeated, then pigs were euthanized and ex vivo studies performed in the stenotic kidney to quantify inflammation, fibrosis, microvascular density and remodeling.
  
  
  RESULTS
  Four weeks of macitentan therapy modestly improved renal blood flow (29%, P = 0.06 versus pre-treatment) and showed protective effects on the renal parenchyma by attenuating inflammation and glomerulosclerosis, reducing apoptosis and tubular casts and improving albuminuria and cortical microvessel density. No overt adverse effects were observed.
  
  
  CONCLUSIONS
  Possibly by inducing a pro-survival renal microenvironment, macitentan increased renal microvascular density, promoted cell survival and decreased injury, which in turn improved stenotic kidney hemodynamics in our model. Our results further support the safety of using macitentan in patients with concomitant chronic renal disease and supported the feasibility of a new strategy that may preserve the stenotic kidney in RVD.
authors.affiliation: The Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Tullos
authors.affiliation: The Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Stewart
authors.affiliation: The Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Davidovich
authors.affiliation: The Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA The Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA The Department of Radiology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Chade
mesh_terms: D000818:Animals; D015153:Blotting, Western; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000737:chemistry* / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000737:chemistry* / Q000378:metabolism; D012078:Renal Artery Obstruction / Q000503:physiopathology; D012079:Renal Circulation / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; C533860:macitentan
keywords: endothelin; imaging microcirculation; inflammation; renal hemodynamics; renovascular disease