DEFECTIVE DOPAMINE-1 RECEPTOR ADENYLATE-CYCLASE COUPLING IN THE PROXIMAL CONVOLUTED TUBULE FROM THE SPONTANEOUSLY HYPERTENSIVE RAT
DEFECTIVE DOPAMINE-1 RECEPTOR ADENYLATE-CYCLASE COUPLING IN THE PROXIMAL CONVOLUTED TUBULE FROM THE SPONTANEOUSLY HYPERTENSIVE RAT
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DOI：
10.1172/jci114371
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发表时间：
1989-12-01
影响因子：
15.9
通讯作者：
FELDER, RA
中科院分区：
文献类型：
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作者：
KINOSHITA, S;SIDHU, A;FELDER, RA
自发性高血压大鼠（SHR）中DA-1受体激动剂的利钠利尿作用低于其正常血压对照大鼠（WKY）。为了确定DA-1激动剂对钠转运作用降低的机制，通过放射性配体结合和腺苷酸环化酶（AC）测定研究了肾近曲小管（PCT）中的DA-1受体。125 I-SCH 23982（由10 μ M SCH 23390，DA-1拮抗剂定义）的特异性结合是浓度依赖性的、可饱和的和立体选择性的。SHR和WKY的解离常数、最大受体密度和DA-1拮抗剂抑制对比度相似。光亲和D1探针125 I-MAB测定的DA-1受体的表观分子量在WKY和SHR中也相似。然而，DA-1激动剂竞争更有效地为特定的125 I-SCH 23982结合位点在WKY比在SHR。基础以及毛喉素，甲状旁腺激素，GTP和GPP（NH）p刺激的AC活动是相似的。相比之下，DA-1激动剂（非诺多泮，SKF 38393，SND 911 c12）刺激AC活动在SHR中的程度较低。GTP和Gpp（NH）p增强DA-1激动剂刺激WKY AC活性的能力，但在SHR中不增强。这些数据表明，在DA-1受体-第二信使耦合机制的缺陷，在PCT的SHR。
The natriuretic effect of DA-1 agonists is less in the spontaneously hypertensive rat (SHR) than its normotensive control, the Wistar-Kyoto rat (WKY). To determine a mechanism of the decreased effect of DA-1 agonists on sodium transport, DA-1 receptors in renal proximal convoluted tubule (PCT) were studied by radioligand binding and by adenylate cyclase (AC) determinations. Specific binding of 125I-SCH 23982 (defined by 10 .mu.M SCH 23390, a DA-1 antagonist) was concentration dependent, saturable, and stereoselective. The dissociation constant, maximum receptor density, and DA-1 antagonist inhibition contrast were similar in SHR and WKY. The apparent molecular weight of the DA-1 receptor determined by the photoaffinity D1 probe 125I-MAB was also similar in WKY and SHR. However, DA-1 agonists competed more effectively for specific 125I-SCH 23982 binding sites in WKY than in SHR. Basal as well as forskolin, parathyroid hormone, GTP and Gpp(NH)p-stimulated-AC activities were similar. In contrast DA-1 agonists (fenoldopam, SKF 38393, SND 911c12) stimulated AC activity to a lesser extent in SHR. GTP and Gpp(NH)p enhanced the ability of DA-1 agonists to stimulate AC activity in WKY but not in SHR. These data suggest a defect in the DA-1 receptor-second messenger coupling mechanism in the PCT of the SHR.