Kassab S, Miller M T, Novak J, Reckelhoff J, Clower B, Granger J P
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Hypertension. 1998 Jan;31(1 Pt 2):397-402. doi: 10.1161/01.hyp.31.1.397.
The aim of this study was to examine the role of endothelin-A (ET(A)) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ET(A) antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118+/-3 to 186+/-15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125+/-4 to 167+/-12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ET(A) receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1+/-1.1 to 74.3+/-5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7+/-1.2 to 55.2+/-6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ET(A) receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.
本研究旨在探讨内皮素A（ET(A)）受体在介导与高盐摄入相关的高血压及肾损伤中所起的作用，该研究以Dahl盐敏感（DS）大鼠作为研究对象。为实现这一目标，我们对给予高钠（8% NaCl）饮食（HSD）3周的DS大鼠和Dahl盐抵抗（DR）大鼠，检测了剂量为10 mg/kg/d的慢性选择性ET(A)拮抗剂（A - 127722）治疗对动脉血压、肾功能及形态学的影响。将DS大鼠（n = 13）置于HSD喂养3周导致收缩压逐渐升高（从118±3升高至186±15 mmHg）。在用A - 127722治疗的DS大鼠（n = 13）中，收缩压的升高显著减弱（从125±4降至167±12 mmHg）。在研究结束时直接测量的平均动脉压（MAP）在接受A - 127722治疗的DS大鼠中也显著降低了18 mmHg（P <.02）。慢性压力 - 利钠曲线的斜率在DS大鼠中向右偏移，而在DS大鼠中通过慢性ET(A)受体阻断使其向左偏移。DS大鼠的高血压与明显的蛋白尿有关（从4.1±1.1增加至74.3±5.3 mg/24 h/100 g体重），在用A - 127722治疗的DS大鼠中蛋白尿显著减弱（从5.7±1.2降至55.2±6.5 mg/24 h/100 g体重）。在用A - 127722治疗后，DS大鼠中显示纤维化、细胞增多和玻璃样变的肾小球百分比也显著降低。置于HSD的DR大鼠在接受ET(A)受体阻断后，动脉血压、蛋白排泄、肾血流动力学及形态结构均无显著变化。这些数据表明，内皮素A受体激活可能在DS大鼠高血压的加重及肾损伤的发展中起作用。
