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

Abstract

1. Chronic treatment with a combined ET_A/ET_B 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 ET_A/ET_B endothelin antagonist may be due in part to blockade of vasorelaxant endothelial ET_B receptors which could in theory reduce the efficacy of endothelin antagonism.

2. In this study the orally active ET_A-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 ET_A/ET_B 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 ET_A/ET_B 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 ET_A/ET_B 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 ET_A receptor antagonist.

3. Blood pressure of DOCA-salt hypertensive rats was lowered by a mean of 24 and of 27 mmHg (P<0.01) by A-127722.5 after 4 weeks of treatment, when given orally at two different doses (10 and 30 mg kg⁻¹ day⁻¹), and by 18 mmHg by LU 135252 50 mg kg⁻¹ day⁻¹.

4. SHR treated with A-127722.5 for 8 weeks starting at 12 weeks of age exhibited the same progressive rise in blood pressure as untreated SHR. Addition of cilazapril resulted in similar reduction of blood pressure in A-127722.5-treated and untreated SHR.

5. Treatment of 1-K 1C hypertensive rats with the dose of LU 135252 which lowered blood pressure in DOCA-salt hypertensive rats did not cause any reduction in blood pressure relative to untreated rats.

6. These results demonstrate that treatment with either dose of the selective ET_A receptor antagonists A-127722.5 or LU 135252 caused reductions in blood pressure similar to those obtained for a combined ET_A/ET_B endothelin antagonist. Blood pressure was lowered only in hypertensive rats known to overexpress vascular endothelin-1 (DOCA-salt hypertensive rats) but not in those which do not (SHR) or only have mild vascular overexpression of endothelin-1 gene (1-K 1C hypertensive rats). Reduction in activity of the renin-angiotensin system in SHR did not sensitize blood pressure to potential hypotensive effects of an ET_A-selective receptor antagonist.

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