Li J S, Turgeon A, Schiffrin E L
MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montréal, University of Montréal, Québec, Canada.
Am J Hypertens. 1998 May;11(5):554-62. doi: 10.1016/s0895-7061(97)00405-6.
Chronic treatment with a combined ET(A) and ET(B) endothelin receptor antagonist blunts hypertension development and small artery hypertrophy in deoxycorticosterone acetate (DOCA)-salt treated rats, in which endothelin-1 is overexpressed in endothelial cells of blood vessels. To determine whether ET(A) receptor antagonism played a predominant role in these findings, in this study the effects of two orally active ET(A) 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 ET(A) selective antagonism induces similar effects to those of combined ET(A)/ET(B) 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 ET(A) 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.
用内皮素（ET）（A）和ET（B）受体联合拮抗剂进行长期治疗，可抑制醋酸去氧皮质酮（DOCA）-盐处理大鼠的高血压发展和小动脉肥大，在这种大鼠的血管内皮细胞中内皮素-1过表达。为了确定ET（A）受体拮抗作用在这些结果中是否起主要作用，在本研究中，评估了两种口服活性ET（A）选择性内皮素受体拮抗剂A-127722.5和LU 135252对DOCA-盐高血压大鼠血压和小动脉结构的影响。自高血压诱导后，大鼠在饮水中接受A-127722.5（30 mg/kg/天）或LU 135252（50 mg/kg/天）。10只未治疗的DOCA-盐高血压大鼠中有3只死亡，而在两个治疗组中无一死亡，且所有大鼠看起来更健康。用尾套法测量，在用A-127722.5治疗4周后，治疗的DOCA-盐高血压大鼠的收缩压比未治疗的DOCA-盐高血压大鼠平均低20 mmHg（P<0.01），用LU 135252治疗则低14 mmHg（P<0.01）。两种药物治疗均未影响心脏和主动脉相对重量。在安装到线肌动描记器上后，在标准化条件下检查肠系膜、冠状动脉、肾和股血管的小动脉，发现DOCA-盐高血压大鼠的小动脉呈现明显的内向性肥厚性重塑。用A-127722.5治疗的DOCA-盐高血压大鼠在检查的四个血管床中具有明显更小的中膜宽度和中膜与管腔比值，用LU 135252治疗的大鼠在肠系膜和肾小动脉中也有这些表现。这些结果表明，在DOCA-盐高血压大鼠中，慢性ET（A）选择性拮抗作用诱导出与ET（A）/ET（B）受体联合拮抗剂相似的效果；即，轻度降低高血压发展并减轻小动脉形态学变化，并且似乎还能提高存活率。这些结果提示ET（A）受体在DOCA-盐高血压大鼠血压升高的内皮素依赖性成分以及该实验性高血压模型中存在的小动脉形态学变化中起作用。
