title: Endothelin axis is upregulated in human and rat right ventricular hypertrophy.
abstract: BACKGROUND
  Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries.
  
  
  OBJECTIVE
  We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium.
  
  
  RESULTS
  RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r(2)=0.838 and r(2)=0.818, respectively; P<0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10(-7,-6,-5) mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (P<0.01).
  
  
  CONCLUSIONS
  Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.
authors.affiliation: Department of Medicine and Pulmonary Hypertension Program, University of Alberta and Mazankowski Alberta Heart Institute, 2C2 WMC, 8440-112 St, Edmonton, Canada. jayan@ualberta.ca
authors.forename: Jayan
authors.initials: J
authors.lastname: Nagendran
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Linda
authors.initials: L
authors.lastname: Webster
authors.forename: Brian
authors.initials: B
authors.lastname: Chiu
authors.forename: Al
authors.initials: A
authors.lastname: Haromy
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Rebeyka
authors.forename: David B
authors.initials: DB
authors.lastname: Ross
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D019332:Endothelin-1 / Q000096:biosynthesis*; D016232:Endothelins / Q000096:biosynthesis* / Q000502:physiology; D005260:Female; D006801:Humans; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism*; D007223:Infant; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051381:Rats; D044022:Receptor, Endothelin A / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*; D016278:Ventricular Function, Right / Q000502:physiology; D055815:Young Adult
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D044022:Receptor, Endothelin A