EFFECT OF CHRONIC TREATMENT WITH 2 DIFFERENT ETA SELECTIVE ENDOTHELINRECEPTOR ANTAGONISTS ON BLOOD-PRESSURE AND SMALL ARTERY STRUCTURE OF DEOXYCORTICOSTERONE ACETATE (DOCA)-SALT HYPERTENSIVE RATS

Chronic treatment with a combined ETA and ETB endothelin receptor anta gonist blunts hypertension development and small artery hypertrophy in deoxycorticosterone acetate (DOCA)-salt treated rats, in which endoth elin-l is overexpressed in endothelial cells of blood vessels. To dete rmine whether ETA receptor antagonism played a predominant role in the se findings, in this study the effects of two orally active ETA select ive endothelin receptor antagonists, A-127722.5 and LU 135252 were eva luated on blood pressure and small artery structure in DOCA-salt hyper tensive rats. Rats received A-127722.5 (30 mg/kg/day) or LU 135252 (50 mg/kg/day) in their drinking water since induction of hypertension. W hereas three of 10 untreated DOCA-salt hypertensive rats died, in the two treated groups none died and all appeared healthier. Systolic bloo d pressure of treated DOCA-salt hypertensive rats, measured with the t ail cuff method, was lower than that of untreated DOCA-salt hypertensi ve rats by a mean of 20 mm Hg (P < .01) after 4 weeks of treatment wit h A-127722.5 and by 14 mm Hg (P < .01) with LU 135252. Cardiac and aor tic relative weights were unaffected by treatment with either agent. S mall arteries of the mesenteric, coronary, renal, and femoral vasculat ure, examined under standardized conditions after mounting on a wire m yograph, were found to exhibit significant inward hypertrophic remodel ing in DOCA-salt hypertensive rats. DOCA-salt hypertensive rats treate d with A-127722.5 had a significantly smaller media width and media-to -lumen ratio in the four vascular beds examined, and rats treated with LU 135252 showed these findings in mesenteric and renal small arterie s. These results demonstrate that chronic ETA selective antagonism ind uces similar effects to those of combined ETA/ETB receptor antagonists in DOCA-salt hypertensive rats; namely, mild reduction in development of hypertension and blunting of small artery morphological changes, a nd also appears to improve survival. These results suggest a role of E TA receptors in the endothelin dependent component of blood pressure e levation in DOCA-salt hypertensive rats, and in the small artery morph ological changes present in this model of experimental hypertension. ( C) 1998 American Journal of Hypertension, Ltd.