Rothermund L, Luckert S, Kossmehl P, Paul M, Kreutz R
Institut für Klinische Pharmakologie und Toxikologie, Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.
Hypertension. 2001 Feb;37(2):275-80. doi: 10.1161/01.hyp.37.2.275.
It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250+/-6 versus 172+/-5 mm Hg, P:<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P:<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U(Na(+))) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P:<0.005, respectively). SHR animals showed a similar increase in both renal ET(A) and ET(B) receptor densities after NX-NaCl (2.2-fold, P:<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET(A) compared with ET(B) binding (4.7-fold versus 2.4-fold, P:<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET(A)/ET(B) receptor ratio only in the SHRSP-NX-NaCl (P:<0.05). Thus, activation of the renal ET system together with an increased ET(A)/ET(B) receptor ratio may contribute to the development and progression of SS-SH.
目前尚不清楚为何一部分原发性高血压患者会随着时间推移，在靶器官损害进展过程中出现盐敏感性高血压。我们评估了肾内皮素（ET）系统在盐敏感性自发性高血压（SS-SH）的易卒中自发性高血压大鼠（SHRSP）模型中所起的作用，并与盐抵抗性自发性高血压（SR-SH）的自发性高血压大鼠（SHR）模型进行了比较。对这两种品系的大鼠，分别在正常饮食下进行假手术（假手术组），或在单侧肾切除并给予高盐负荷（NX-NaCl）后，即饮食中含4% NaCl持续6周（每组n = 10）进行研究。与SHRSP-假手术组相比（172±5 mmHg），收缩压（SBP）仅在SHRSP-NX-NaCl组中升高（250±6 mmHg，P < 0.0001）。与SHR-假手术组相比，SHR-NX-NaCl组的SBP保持不变。在SHRSP-NX-NaCl组动物中，与SHRSP-假手术组相比，尿白蛋白和ET-1排泄量、肾ET-1 mRNA表达、肾小球硬化指数和肾小管间质损伤指数均升高（P均< 0.05），而在SHR的NX-NaCl组中未发现显著变化。与SHR-NX-NaCl组相比，SHRSP-NX-NaCl组的尿钠排泄量（U(Na+)）显著降低38%（P < 0.005）。在NX-NaCl组后，SHR动物肾ET(A)和ET(B)受体密度均有类似程度的增加（2.2倍，P < 0.05）。相比之下，与SHRSP-假手术组相比，SHRSP-NX-NaCl组ET(A)结合的增加明显高于ET(B)结合（分别为4.7倍和2.4倍，P < 0.05），仅在SHRSP-NX-NaCl组中ET(A)/ET(B)受体比值显著增加2.1倍（P < 0.05）。因此，肾ET系统的激活以及ET(A)/ET(B)受体比值的增加可能促成了SS-SH的发生和进展。
