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(Circulation. 2002;106:2305.)
© 2002 American Heart Association, Inc.

Brief Rapid Communications

Endothelin-A Receptor Blockade Prevents Left Ventricular Hypertrophy and Dysfunction in Salt-Sensitive Experimental Hypertension

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

From the Institut für Klinische Pharmakologie (L.R., M.D., P.K., Ö.G., R.K.) und Toxikologie (R.V.), Medizinische Klinik IV Nephrologie (L.R., R.K.), Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany; and Laboratory for Molecular Medicine and Department of Nephrology and Hypertension (C.Y., Y.Y.), Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon, Israel.

Correspondence to Reinhold Kreutz, MD, FAHA, Benjamin Franklin Klinikum, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail Kreutz{at}medizin.fu-berlin.de

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.

Key Words: hypertension • endothelin • heart failure • sodium

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