1. 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. 2. 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 IC) 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. 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 IC 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 ETA receptor antagonists
A-127722.5 or
LU 135252 caused reductions in blood pressure similar to those obtained for a combined ETA/ETB
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 ETA-selective receptor antagonist.