Effect of chronic treatment with two different ETA selective endothelin receptor antagonists on blood pressure and small artery structure of deoxycorticosterone acetate (DOCA)-salt hypertensive rats

被引:27
作者
Li, JS [1 ]
Turgeon, A [1 ]
Schiffrin, EL [1 ]
机构
[1] Univ Montreal, Clin Res Inst Montreal, MRC, Multidisciplinary Res Grp Hypertens, Montreal, PQ H2W 1R7, Canada
基金
英国医学研究理事会;
关键词
endothelin-1; blood vessels; vascular remodeling;
D O I
10.1016/S0895-7061(97)00405-6
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Chronic treatment with a combined ETA and ETB endothelin receptor antagonist blunts hypertension development and small artery hypertrophy in deoxycorticosterone acetate (DOCA)-salt treated rats, in which endothelin-l is overexpressed in endothelial cells of blood vessels. To determine whether ETA receptor antagonism played a predominant role in these findings, in this study the effects of two orally active ETA selective endothelin receptor antagonists, A-127722.5 and LU 135252 were evaluated on blood pressure and small artery structure in DOCA-salt hypertensive 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. Whereas three of 10 untreated DOCA-salt hypertensive rats died, in the two treated groups none died and all appeared healthier. Systolic blood pressure of treated DOCA-salt hypertensive rats, measured with the tail cuff method, was lower than that of untreated DOCA-salt hypertensive rats by a mean of 20 mm Hg (P < .01) after 4 weeks of treatment with A-127722.5 and by 14 mm Hg (P < .01) with LU 135252. Cardiac and aortic relative weights were unaffected by treatment with either agent. Small arteries of the mesenteric, coronary, renal, and femoral vasculature, examined under standardized conditions after mounting on a wire myograph, were found to exhibit significant inward hypertrophic remodeling in DOCA-salt hypertensive rats. DOCA-salt hypertensive rats treated 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 arteries. These results demonstrate that chronic ETA selective antagonism induces 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, and also appears to improve survival. These results suggest a role of ETA receptors in the endothelin dependent component of blood pressure elevation in DOCA-salt hypertensive rats, and in the small artery morphological changes present in this model of experimental hypertension. (C) 1998 American Journal of Hypertension, Ltd.
引用
收藏
页码:554 / 562
页数:9
相关论文
共 36 条
[1]   ETB RECEPTORS ON AORTIC SMOOTH-MUSCLE CELLS OF SPONTANEOUSLY HYPERTENSIVE RATS [J].
BATRA, VK ;
MCNEILJ, JR ;
XU, YJ ;
WILSON, TW ;
GOPALAKRISHNAN, V .
AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 264 (02) :C479-C484
[2]   REMODELING OF CEREBRAL ARTERIOLES IN CHRONIC HYPERTENSION [J].
BAUMBACH, GL ;
HEISTAD, DD .
HYPERTENSION, 1989, 13 (06) :968-972
[3]   ANTIHYPERTENSIVE EFFECTS OF A NOVEL ENDOTHELIN-A RECEPTOR ANTAGONIST IN RATS [J].
BIRD, JE ;
MORELAND, S ;
WALDRON, TL ;
POWELL, JR .
HYPERTENSION, 1995, 25 (06) :1191-1195
[4]   GROWTH-FACTOR ACTIVITY OF ENDOTHELIN ON VASCULAR SMOOTH-MUSCLE [J].
BOBIK, A ;
GROOMS, A ;
MILLAR, JA ;
MITCHELL, A ;
GRINPUKEL, S .
AMERICAN JOURNAL OF PHYSIOLOGY, 1990, 258 (03) :C408-C415
[5]   Effects of endothelin receptor inhibition on cerebral arterioles in hypertensive rats [J].
Chillon, JM ;
Heistad, DD ;
Baumbach, GL .
HYPERTENSION, 1996, 27 (03) :794-798
[6]   ENDOTHELIN STIMULATES PROTEIN-SYNTHESIS IN SMOOTH-MUSCLE CELLS [J].
CHUA, BHL ;
KREBS, CJ ;
CHUA, CC ;
DIGLIO, CA .
AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 262 (04) :E412-E416
[7]   IN-SITU HYBRIDIZATION SHOWS INCREASED ENDOTHELIN-1 MESSENGER-RNA LEVELS IN ENDOTHELIAL-CELLS OF BLOOD-VESSELS OF DEOXYCORTICOSTERONE ACETATE-SALT HYPERTENSIVE RATS [J].
DAY, R ;
LARIVIERE, R ;
SCHIFFRIN, EL .
AMERICAN JOURNAL OF HYPERTENSION, 1995, 8 (03) :294-300
[8]  
DENG LY, 1992, AM J PHYSIOL, V262, pH1782
[9]  
DENUCCI G, 1988, P NATL ACAD SCI USA, V85, P9797
[10]   MECHANICS OF LARGE AND SMALL CEREBRAL-ARTERIES IN CHRONIC HYPERTENSION [J].
HAJDU, MA ;
BAUMBACH, GL .
AMERICAN JOURNAL OF PHYSIOLOGY, 1994, 266 (03) :H1027-H1033