Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1.
Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1.
复制标题
对比药理学 ETB 受体阻断与遗传性 ETB 缺陷对大 ET-1 的肾脏反应。
DOI：
10.1152/physiolgenomics.2001.6.1.39
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发表时间：
2001
期刊：
影响因子：
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通讯作者：
Pollock,DM
中科院分区：
文献类型：
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作者：
Pollock,DM
进行肾清除研究以确定ETB受体在肾对大内皮素-1（big ET-1）的反应中的作用。在Inactin麻醉的大鼠上进行了两个系列的实验，以对比ETB受体的急性药理学阻断与遗传性ETB受体缺乏。在第一个系列中，给予Sprague-Dawley大鼠ETB选择性拮抗剂A-192621或溶媒（0.9% NaCl），然后输注大ET-1（10 pmol·kg−1·min−1）给药60 min。A-192621显著升高基线平均动脉压（MAP：102 ± 4 vs. 141 ± 6 mmHg，P< 0.05）和尿流率（0.5 ± 0.1 vs. 1.3 ± 0.2 μl/min，P< 0.05）对肾小球滤过率（GFR）和有效肾血浆流量（ERPF）无任何影响。大ET-1使两组大鼠MAP均明显升高，但拮抗剂组升高幅度更大（120 ± 6vs.169 ± 6 mmHg，P< 0.05）。大ET-1使对照组大鼠尿量增加，而拮抗剂组大鼠尿量减少。给予大剂量ET-1的大鼠GFR和ERPF降低，而阻断ET-1则加重了这种作用。另一系列实验检测了缺乏功能性肾ETB受体的大鼠（称为斑点致死（sl）大鼠）对大ET-1的反应。令人惊讶的是，ETB受体缺陷的杂合子（sl/+）大鼠与纯合子（sl/sl）大鼠相比具有显著更高的基线MAP（134 ± 6vs.112 ± 7 mmHg，P< 0.05），尽管其他变量相似。大ET-1对两组MAP无明显影响。两组的尿流量、GFR和ERPF均显著降低，尽管这些变化在大鼠中要大得多。这些实验表明，ET-1受体在限制大ET-1引起的肾血流动力学反应中起重要作用。此外，大ET-1的利尿作用需要功能性ET B受体。
Renal clearance studies were conducted to determine the role of ETBreceptors in the renal response to big endothelin-1 (big ET-1). Two series of experiments were conducted on Inactin-anesthetized rats to contrast acute pharmacological blockade of ETBreceptors vs. genetic ETBreceptor deficiency. In the first series, Sprague-Dawley rats were given either ETB-selective antagonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of big ET-1 (10 pmol·kg−1·min−1) for 60 min. A-192621 significantly increased baseline mean arterial pressure (MAP; 102 ± 4 vs. 141 ± 6 mmHg,P< 0.05) and urine flow rate (0.5 ± 0.1 vs. 1.3 ± 0.2 μl/min,P< 0.05) without any effect on glomerular filtration rate (GFR) or effective renal plasma flow (ERPF). Big ET-1 significantly increased MAP in both groups but to a higher level in rats given antagonist (120 ± 6 vs. 169 ± 6 mmHg,P< 0.05). Big ET-1 increased urine flow in control rats but decreased in rats given antagonist. GFR and ERPF were decreased in rats given big ET-1, an effect that was exaggerated by ETBblockade. Another series of experiments examined the response to big ET-1 in rats lacking functional renal ETBreceptors, known as spotting lethal (sl) rats. Surprisingly, rats heterozygous (sl/+) for ETBreceptor deficiency had a significantly higher baseline MAP compared with homozygous (sl/sl) rats (134 ± 6 vs. 112 ± 7 mmHg,P< 0.05), although other variables were similar. Big ET-1 produced no significant change in MAP in either group. Urine flow, GFR, and ERPF were significantly decreased in both groups, although these changes were much larger insl/slrats. These experiments indicate that the ETBreceptor plays an important role in limiting the renal hemodynamic response to big ET-1. Furthermore, the diuretic actions of big ET-1 require a functional ETBreceptor.