EFFECT OF CHRONIC ETA-SELECTIVE ENDOTHELIN RECEPTOR ANTAGONISM ON BLOOD-PRESSURE IN EXPERIMENTAL AND GENETIC-HYPERTENSION IN RATS

1 Chronic treatment with a combined ETA/ETB endothelin receptor antago nist has been shown to reduce blood pressure in experimental rat model s of hypertension in which endothelin-1 gene overexpression occurs in the walls of blood vessels, particularly small, resistance-sized arter ies, but not in those genetic or experimental models of hypertension i n which there is no overexpression of vascular endothelin-1. Failure o f some experimental models of hypertension to respond to treatment wit h the combined ETA/ETB endothelin antagonist may be due in part to blo ckade of vasorelaxant endothelial ETB receptors which could in theory reduce the efficacy of endothelin antagonism. 2 In this study the oral ly active ETA-selective endothelin antagonists A-127722.5 and LU 13525 2 were used in chronic experiments on deoxycorticosterone acetate (DOC A)-salt hypertensive rats (which overexpress vascular endothelin-1 and respond with blood pressure lowering to combined ETA/ETB endothelin r eceptor antagonism), on spontaneously hypertensive rats (SHR) (which d o 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 m ild overexpression of vascular endothelin-1 but do not respond with bl ood pressure lowering to the combined ETA/ETB receptor antagonist). Ad ditionally, it has been suggested that interruption of the renin-angio tensin system may sensitize responses to endothelin antagonism. Accord ingly, SHR were treated with an angiotensin converting enzyme inhibito r, cilazapril, in addition to the ETA receptor antagonist. 3 Blood pre ssure of DOCA-salt hypertensive rats was lowered by a mean of 24 and o f 27 mmHg (P < 0.01) by A-127722.5 after 4 weeks of treatment, when gi ven orally at two different doses (10 and 30 mg kg(-1) day(-1)), and b y 18 mmHg by LU 135252 50 mg kg(-1) day(-1). 4 SHR treated with A-1277 22.5 for 8 weeks starting at 12 weeks of age exhibited the same progre ssive 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 do se of LU 135252 which lowered blood pressure in DOCA-salt hypertensive rats did not cause any reduction in blood pressure relative to untrea ted rats. 6 These results demonstrate that treatment with either dose of the selective ETA receptor antagonists A-127722.5 or LU 135252 caus ed reductions in blood pressure similar to those obtained for a combin ed ETA/ETB endothelin antagonist. Blood pressure was lowered only in h ypertensive rats known to overexpress vascular endothelin-1 (DOCA-salt hypertensive rats) but not in those which do not (SHR) or only have m ild vascular overexpression of endothelin-1 gene (1-K 1C hypertensive rats). Reduction in activity of the renin-angiotensin system in SHR di d not sensitize blood pressure to potential hypotensive effects of an ETA-selective receptor antagonist.