Fenoldopam is a partial agonist at dopamine-1 (DA1) receptors in LLC-PK1 cells.
Fenoldopam is a partial agonist at dopamine-1 (DA1) receptors in LLC-PK1 cells.
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发表时间：
1991-07
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通讯作者：
A. Grenader;D. Healy
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作者：
A. Grenader;D. Healy
非诺多泮[6-氯-7，8-二羟基-1-（4 '-羟基苯基）-2，3，4，5-四氢-（1H）-3-苯并氮杂卓]是一种选择性多巴胺-1（DA 1）激动剂，具有利钠/利尿特性。对非诺多泮的利钠反应的一个组成部分可能涉及对近端小管钠重吸收的直接DA 1受体介导的作用，可能通过刺激腺苷酸环化酶。在这里，我们比较了非诺多泮和DA在LLC-PK 1细胞中刺激环腺苷酸（cAMP）合成的作用，LLC-PK 1细胞是一种肾上皮细胞系，具有近端小管样特性，并表达与腺苷酸环化酶刺激相关的DA 1受体。非诺多泮以剂量依赖性方式刺激LLC-PK 1细胞中的cAMP积累，这种作用可以被DA 1选择性拮抗剂Sch 23390阻断。虽然非诺多泮比DA更有效（EC 50 55.5 +/- 7.75 nM vs. 1.65 +/- 0.64 microM）刺激LLC-PK 1细胞中cAMP积累，非诺多泮获得的最大刺激仅为DA获得的最大刺激的37（Emax 13.0 +/- 2.95 pmol/mg蛋白vs. 35.6 +/- 10.19 pmol/mg蛋白）。DA和非诺多泮同时孵育导致cAMP水平低于单独DA。孵育DA与浓度增加的非诺多泮产生平行的DA剂量-反应曲线的位移。Schild分析进一步表明，在DA存在下，非诺多泮作为竞争性拮抗剂，pA 2值为7.38，斜率为1。这些结果表明，非诺多泮是一种部分激动剂，对LLC-PK 1细胞中与cAMP生成相关的DA 1受体的效力较低。
Fenoldopam [6-chloro-7,8-dihydroxy-1-(4'-hydroxyphenyl)-2, 3,4,5-tetrahydro-(1H)-3-benzazepine] is a selective dopamine-1 (DA1) agonist with natriuretic/diuretic properties. A component of the natriuretic response to fenoldopam may involve direct DA1 receptor-mediated effects on proximal tubule sodium reabsorption, possibly through stimulation of adenylyl cyclase. Here, we compared the effects of fenoldopam and DA in stimulating cyclic AMP (cAMP) synthesis in LLC-PK1 cells, a renal epithelial cell line that has proximal tubule-like properties and expresses a DA1 receptor linked to stimulation of adenylyl cyclase. Fenoldopam stimulated cAMP accumulation in LLC-PK1 cells in a dose-dependent manner, an effect which could be blocked by the DA1-selective antagonist Sch 23390. Although fenoldopam was more potent than DA (EC50 55.5 +/- 7.75 nM vs. 1.65 +/- 0.64 microM) in stimulating cAMP accumulation in LLC-PK1 cells, the maximum stimulation obtained by fenoldopam was only 37% of the maximum stimulation obtained by DA(Emax 13.0 +/- 2.95 pmol/mg of protein vs. 35.6 +/- 10.19 pmol/mg of protein). Simultaneous incubation of DA and fenoldopam resulted in lower cAMP levels than with DA alone. Incubation of DA with increasing concentrations of fenoldopam produced parallel rightward shifts in the DA dose-response curves. Schild analysis further indicated that fenoldopam acted as a competitive antagonist in the presence of DA, with a pA2 value of 7.38 and a slope of unity. These results indicate that fenoldopam is a partial agonist with low efficacy at DA1 receptors linked to cAMP generation in the LLC-PK1 cells.