长期输注肾上腺髓质素可提高恶性高血压大鼠的存活率。

Mori Yosuke, Nishikimi Toshio, Kobayashi Naohiko, Ono Hidehiko, Kangawa Kenji, Matsuoka Hiroaki

Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.

Hypertension. 2002 Jul;40(1):107-13. doi: 10.1161/01.hyp.0000023226.50264.42.

Previous studies have demonstrated that adrenomedullin has inhibitory effects on the proliferation and DNA synthesis of mesangial cells and vascular smooth muscle cells in vitro and that plasma adrenomedullin levels are markedly elevated in malignant hypertension. This study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in malignant hypertensive rats. We studied the following 3 groups: control Wistar Kyoto rats, deoxycorticosterone acetate-salt spontaneously hypertensive rats, and adrenomedullin-treated deoxycorticosterone acetate-salt spontaneously hypertensive rats. Chronic adrenomedullin infusion using an osmotic minipump was started simultaneously with deoxycorticosterone acetate-salt treatment. After 3 weeks of the treatment, malignant hypertensive rats were characterized by higher blood pressure, kidney weight, urinary protein excretion, glomerular injury score, plasma renin concentration, aldosterone level, endogenous rat plasma adrenomedullin level, renal cortical tissue angiotensin II level, angiotensin-converting enzyme mRNA level, and transforming growth factor-beta1 mRNA level in the renal cortex, and by lower creatinine clearance, compared with the control rats. Chronic adrenomedullin infusion significantly improved these parameters (kidney weight -6.5%, urinary protein excretion -63.8%, glomerular injury score -38.3%, plasma renin concentration -52.4%, aldosterone -23.2%, rat adrenomedullin -28.6%, renal angiotensin II -28.1%, renal angiotensin-converting enzyme mRNA -38.3%, renal transforming growth factor-beta1 mRNA -56.2%, and creatinine clearance +20.5%) without significant reduction of mean arterial pressure (-4%). Kaplan-Meier survival analysis showed that adrenomedullin infusion significantly prolonged survival time. These results suggest that subdepressor dose of chronic adrenomedullin infusion has renoprotective effects in this malignant hypertension model, at least in part, via inhibition of the circulating and intrarenal renin-angiotensin system.

以往的研究表明，肾上腺髓质素在体外对系膜细胞和血管平滑肌细胞的增殖及DNA合成具有抑制作用，且在恶性高血压患者中血浆肾上腺髓质素水平显著升高。本研究旨在探讨慢性输注肾上腺髓质素对恶性高血压大鼠是否具有肾脏保护作用。我们研究了以下3组：对照Wistar Kyoto大鼠、醋酸脱氧皮质酮-盐自发性高血压大鼠以及肾上腺髓质素治疗的醋酸脱氧皮质酮-盐自发性高血压大鼠。使用渗透微型泵进行慢性肾上腺髓质素输注与醋酸脱氧皮质酮-盐治疗同时开始。治疗3周后，与对照大鼠相比，恶性高血压大鼠的特征为血压更高、肾脏重量增加、尿蛋白排泄增加、肾小球损伤评分升高、血浆肾素浓度升高、醛固酮水平升高、内源性大鼠血浆肾上腺髓质素水平升高、肾皮质组织血管紧张素II水平升高、血管紧张素转换酶mRNA水平升高以及肾皮质中转化生长因子-β1 mRNA水平升高，而肌酐清除率降低。慢性肾上腺髓质素输注显著改善了这些参数（肾脏重量降低6.5%、尿蛋白排泄降低63.8%、肾小球损伤评分降低38.3%、血浆肾素浓度降低52.4%、醛固酮降低23.2%、大鼠肾上腺髓质素降低28.6%、肾血管紧张素II降低28.1%、肾血管紧张素转换酶mRNA降低38.3%、肾转化生长因子-β1 mRNA降低56.2%以及肌酐清除率升高20.5%），而平均动脉压无显著降低（降低4%）。Kaplan-Meier生存分析表明，肾上腺髓质素输注显著延长了生存时间。这些结果提示，在该恶性高血压模型中，亚降压剂量的慢性肾上腺髓质素输注至少部分通过抑制循环和肾内肾素-血管紧张素系统而具有肾脏保护作用。