Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease
Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease
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DOI：
10.1093/ndt/gfm364
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发表时间：
2007-11-01
影响因子：
6.1
通讯作者：
Webb, David J.
中科院分区：
文献类型：
--
作者：
Dhaun, Neeraj;Ferro, Charles J.;Webb, David J.
背景资料。内皮素-1(ET-1)参与了慢性肾脏疾病(CKD)的病理生理过程，阻断ET受体对动物具有肾脏保护作用。我们检测了ET受体拮抗剂TAK-044对CKD患者的血流动力学和肾脏的影响。在一项随机双盲交叉研究中，7名CKD患者(平均动脉压103毫米汞柱；平均血肌酐3.5毫克/分升)接受了三次15分钟的静脉注射，每次间隔至少7天，要么是安慰剂，要么是TAK-044(100或750毫克)。分别于注射安慰剂和药物前后检测全身和肾脏血流动力学、血浆免疫反应性ET-1、BIG ET-1和C末端片段浓度。与安慰剂相比，TAK-044降低了平均动脉压(MAP)(100 mg：7.4+/-1.9 mm Hg，750 mg：8.4+-2.3 mm Hg，P<；0.01)和全身血管阻力指数(100 mg：650+/-140 dyne.cm(-5))。M(-2)，750 mg：829+/-141dyne.s.cm-5。M-2，P<；0.01)。Tak-044在两种剂量下对心脏指数和心率的增加程度相似。在肾血流动力学方面，TAK-044对肾小球滤过率无明显影响，但呈剂量依赖性地增加肾血浆流量(100 mg：9.6+/-5.0ml/min，750 mg：25.3+/-19.5ml/min)，降低有效滤过分数(100 mg：3.6+/-1.1%，750 mg：4.7+/-1.7%，P<；0.01)。Tak-044对钠或锂的排泄率或钠和锂的排泄分数没有显著影响。服用750 mg TAK-044后，血浆ET-1浓度升高2倍以上，而大片段ET-1和C末端浓度无明显变化。这些发现提示ET-1在控制CKD患者的全身和肾脏血流动力学方面起着重要作用。这项研究显示的ET受体拮抗剂的降压和潜在的肾脏保护作用可能被证明在减缓CKD的进展方面是有用的。现在需要临床试验来解决CKD的这些关键问题。
Background. Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD.Methods. Seven patients with CKD (mean arterial pressure 103mmHg; mean plasma creatinine 3.5mg/dl) received three 15min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs.Results. Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100mg: 7.4 +/- 1.9mmHg, 750 mg: 8.4 +/- 2.3mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5). m(-2), 750 mg: 829 +/- 141 dyne.s.cm-5. m-2, P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged.Conclusions. These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.