title: Endothelin-A receptor blockade prevents left ventricular hypertrophy and dysfunction in salt-sensitive experimental hypertension.
abstract: BACKGROUND
  Salt-sensitive hypertension represents a major cause of left ventricular (LV) dysfunction. We therefore explored the potential effects of the selective endothelin-A (ETA) receptor antagonist darusentan on the development of hypertension, LV hypertrophy (LVH), and dysfunction in a genetic rat model of salt-sensitive hypertension.
  
  
  RESULTS
  Animals from the salt-sensitive Sabra rat strain (SBH/y) and the salt-resistant strain (SBN/y) were treated with either normal diet (SBH/y and SBN/y) or with deoxycorticosterone-acetate (DOCA) and salt (SBN/y-DOCA and SBH/y-DOCA). Additional groups were treated with 50 mg x kg(-1) x d(-1) of darusentan (SBH/y-DOCA-DA and SBN/y-DOCA-DA). Systolic blood pressure and LV weight increased in response to DOCA only in the SBH/y strain (+75 mm Hg and +30%; P<0.05). LV end-diastolic pressure increased and -dP/dtmax decreased in SBH/y-DOCA compared with SBH/y (P<0.05). This was paralleled by a 5-fold upregulation of LV mRNA expression of atrial natriuretic factor (ANF) and a significant reduction of sarcoplasmic reticulum (SR) Ca2+-reuptake and the SR Ca2+-ATPase to phospholamban protein ratio (-30%). Whereas treatment with darusentan in SBH/y-DOCA-DA reduced the SBP increase by 50%, LVH elevation of ANF mRNA and LV dysfunction were completely prevented (P<0.05); this was associated with a normalization of SR Ca2+-reuptake and SR Ca2+-ATPase to phospholamban ratio by darusentan (P<0.05). A moderate elevation of interstitial fibrosis in SBH/y-DOCA (P<0.05) remained unaffected by darusentan treatment.
  
  
  CONCLUSIONS
  In the Sabra model of salt-sensitive hypertension, ETA-receptor blockade demonstrated striking effects on the prevention of LVH and LV dysfunction beyond its considerable antihypertensive effect.
authors.affiliation: Institut für Klinische Pharmakologie, Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Rothermund
authors.forename: Roland
authors.initials: R
authors.lastname: Vetter
authors.forename: Maike
authors.initials: M
authors.lastname: Dieterich
authors.forename: Peter
authors.initials: P
authors.lastname: Kossmehl
authors.forename: Ozlem
authors.initials: O
authors.lastname: Gögebakan
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis / Q000209:etiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D044022:Receptor, Endothelin A; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012965:Sodium Chloride; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D000099211:Phospholamban
chemical_list: D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012965:Sodium Chloride; D000099211:Phospholamban; C107831:darusentan