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. 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) Ca 2+ -reuptake and the SR Ca 2+ -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 Ca 2+ -reuptake and SR Ca 2+ -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.