Effect of chronic ETA‐selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats

Chronic treatment with a combined ETA/ETB endothelin receptor antagonist has been shown to reduce blood pressure in experimental rat models of hypertension in which endothelin‐1 gene overexpression occurs in the walls of blood vessels, particularly small, resistance‐sized arteries, but not in those genetic or experimental models of hypertension in which there is no overexpression of vascular endothelin‐1. Failure of some experimental models of hypertension to respond to treatment with the combined ETA/ETB endothelin antagonist may be due in part to blockade of vasorelaxant endothelial ETB receptors which could in theory reduce the efficacy of endothelin antagonism. In this study the orally active ETA‐selective endothelin antagonists A‐127722.5 and LU 135252 were used in chronic experiments on deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (which overexpress vascular endothelin‐1 and respond with blood pressure lowering to combined ETA/ETB endothelin receptor antagonism), on spontaneously hypertensive rats (SHR) (which do not overexpress vascular endothelin‐1 and do not respond with blood pressure lowering to the combined ETA/ETB receptor antagonist), and in 1‐kidney 1 clip Goldblatt (1‐K 1C) hypertensive rats (which present mild overexpression of vascular endothelin‐1 but do not respond with blood pressure lowering to the combined ETA/ETB receptor antagonist). Additionally, it has been suggested that interruption of the renin‐angiotensin system may sensitize responses to endothelin antagonism. Accordingly, SHR were treated with an angiotensin converting enzyme inhibitor, cilazapril, in addition to the ETA receptor antagonist. Blood pressure of DOCA‐salt hypertensive rats was lowered by a mean of 24 and of 27 mmHg (P