Published Online
on October 14, 2002

A more recent version of this article appeared on October 29, 2002

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Submitted on July 10, 2002
Revised on September 3, 2002
Accepted on September 9, 2002

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, and 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.

^* To whom correspondence should be addressed. 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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