Endothelin-A receptor blockade prevents left ventricular hypertrophy and dysfunction in salt-sensitive experimental hypertension

Lars Rothermund, Roland Vetter, Maike Dieterich, Peter Kossmehl, Özlem Gögebakan, Chana Yagil, Yoram Yagil, Reinhold Kreutz

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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. Methods and 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·kg-1·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. Conclusion - 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.

Original languageEnglish
Pages (from-to)2305-2308
Number of pages4
Issue number18
StatePublished - 29 Oct 2002
Externally publishedYes


  • Endothelin
  • Heart failure
  • Hypertension
  • Sodium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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