从多巴胺受体的研究成果看高血压治疗的新对策

肾脏是人体负责钠排泄的重要器官,近年研究发现肾脏的利尿、排钠作用受到多巴胺的控制。所有多巴胺受体亚型均直接或间接参与血压调节和肾脏尿钠排泄。本文旨在探讨多巴胺受体在原发性高血压发生中的作用,以及多巴胺与其相关调节因子在原发性高血压防治方面的应用前景。     

多巴胺D3受体对肾脏近曲小管上皮细胞D5受体的影响在高血压发生中的作用

目的 观察多巴胺D3受体对肾脏近曲小管(RPT)上皮细胞上多巴胺D5受体表达和功能的影响. 方法 以Wistar-Kyoto(WKY)大鼠与自发性高血压大鼠(SHR)为研究对象,利用免疫印迹法观察D3受体对D5受体蛋白表达的影响;并采用Na -K -ATP酶活性测定方法在转染D5受体的人胚肾293细胞(HEK293-D5)上观察D3受体对D5受体影响的病理生理学意义. 结果 刺激D3受体可增强D5受体的蛋白表达,该作用呈浓度和时间依赖性;同时能被D3受体特异性阻断剂所阻断;在高血压状态下,这种作用受损.刺激D5受体可抑制Na -K -ATP酶的活性,在预先刺激D3受体的情况下可使D5受体对Na -K -ATP酶活性的抑制作用进一步增强. 结论 D3受体对肾脏近曲小管上皮细胞上D5受体的表达和功能具有促进作用,这种作用的受损可能在原发性高血压的发生发展中具有一定影响.     

从多巴胺受体的研究成果看高血压治疗的新对策

肾脏是人体负责钠排泄的重要器官,近年研究发现肾脏的利尿、排钠作用受到多巴胺的控制.所有多巴胺受体亚型均直接或间接参与血压调节和肾脏尿钠排泄.本文旨在探讨多巴胺受体在原发性高血压发生中的作用,以及多巴胺与其相关调节因子在原发性高血压防治方面的应用前景.     

多巴胺受体与其他血压调节系统的交互作用在高血压研究中的地位

肾脏是人体负责钠排泄的重要器官,多巴胺由于其强大的抑制肾脏钠重吸收作用而在原发性高血压的发生、发展中发挥重要作用。多巴胺受体的5个亚型均直接或间接通过与其他血压调节系统的交互作用,参与肾脏钠通道或血压的调节。现就多巴胺受体在调节机体血压和肾脏利钠、利尿作用中所发挥的重要作用作一综述。     

肾脏内皮素B受体参与D3受体介导WKY大鼠尿钠排泄调节

目的 肾脏多巴胺和内皮素(ET)系统通过影响近曲小管尿钠排泄在血压调节中发挥重要作用.敲除ETB受体基因或D3多巴胺受体基因均形成盐敏感性高血压小鼠,并伴有尿钠排泄能力降低;本试验将探索D3受体和ETB受体之间是否存在相互作用以及该作用对WKY大鼠尿钠排泄的影响.方法 应用D3受体激动剂、拮抗剂和ETB受体拮抗剂灌注WKY大鼠右肾动脉,观察刺激、抑制D3、ETB受体后WKY肾功能尤其是尿钠排泄的变化.结果 PD128907刺激D3受体后,WKY尿钠排泄增加,PD128907介导的促尿钠排泄作用可被D3受体拮抗剂GR103691所阻断;ETB受体拮抗剂BQ788本身对尿钠排泄无明显影响,但可部分阻断D3受体介导的利钠作用.结论 D3受体的促尿钠排泄作用部分通过ETB受体完成.     

多巴胺D_5受体与高血压研究进展

<正>多巴胺是促尿钠排泄的重要体液因子,与其受体结合后,可通过对尿钠重吸收的调节作用,进而调控血压水平〔1〕。多巴胺受体分为D1类(D1和D5受体)和D2类(D2、D3和D4受体),主要通过D1类受体发挥作用。近年来,D5受体在血压调控中的作用日益受到关注。本文就D5受体与高血压的研究进展作一综述。1多巴胺D5受体的特点D5受体和其他多巴胺受体均属于视紫红质类家族,为细     

多巴胺D3受体激动剂对肾脏G蛋白亚基Goα12、Gα13与D3受体耦联的影响

目的观察多巴胺D3受体激动剂对肾脏G蛋白亚基Gα12和Gα13与D3受体耦联的影响。方法以WKY（Wistar-Kyoto）大鼠与自发性高血压大鼠（SHR）及其来源的肾脏皮质膜、肾脏刷状缘膜（BBM）以及近曲小管上皮细胞株（RPT）为研究对象，利用多巴胺D3受体激动剂PD128907刺激D3受体，运用免疫共沉淀观察PD128907对D3受体与Gα12、Gα13的相互关联的影响．并在WKY与SHR中对比关联改变与功能差异。结果D3／Gα12与D3／Gα13之间仵WKY与SHR中均存在共连接。PD128907刺激D3受体后，在WKY中可明显增加D3／Gα12以及D3/Gα13之间的连接程度；在SHR中却显著降低D3／Gα12以及D3／Gα13之间的连接。其中，D3／Gα13在SHR中的基础连接程度明显强于WKY，D3／Gα12连接基础状态在WKY与SHR之间无明显差异。采用PD128907直接灌注WKY和SHR大鼠右肾动脉．发现PDl28907可以明显增强WKY的尿钠排泄率（FENa），但却对SHR的FENa没有影响。结论D3受体激动剂可明届调节D3／Gα12以及D3／Gα13之间的连接程度，该调节作用异常可能在高血压的发生发展中发挥一定作用。     

多巴胺D3受体激动剂对肾脏G蛋白亚基Gα12、Gα13与D3受体耦联的影响

目的 观察多巴胺D3受体激动剂对肾脏G蛋白亚基Galz和Ga13与D3受体耦联的影响. 方法 以WKY(Wistar-Kyoto)大鼠与自发性高血压大鼠(SHR)及其来源的肾脏皮质膜、肾脏刷状缘膜(BBM)以及近曲小管上皮细胞株(RPT)为研究对象,利用多巴胺D3受体激动剂PDl28907刺激D3受体,运用免疫共沉淀观察PD128907对D3受体与Ga12、Ga13的相互关联的影响,并在WKY与SHR中对比关联改变与功能差异. 结果 D3/Ga12与D3/Ga13之间在WKY与SHR中均存在共连接.PDl28907刺激D3受体后,在WKY中可明显增加D3/Ga12以及D3/Ga13之间的连接程度;在SHR中却显著降低D3/Ga12以及93/Ga13之间的连接.其中,D3/Ga13在SHR中的基础连接程度明显强于WKY,D3/Ga12连接基础状态在WKY与SHR之间无明显差异.采用PD128907直接灌注WKY和SHR大鼠右肾动脉,发现PD128907可以明显增强WKY的尿钠排泄率(FENa),但却对SHR的FENa没有影响. 结论 D3受体激动剂可明显调节D3/Ga12以及D3/Ga13之间的连接程度,该调节作用异常可能在高血压的发生发展中发挥一定作用.     

D3多巴胺受体基因敲除小鼠高血压产生机制的探讨

目的探讨D3多巴胺受体基因敲除小鼠（D3-/-）高血压产生的机制,以期了解D3多巴胺受体对血压的调节作用.方法以第2代D3-/-小鼠为研究对象,分别对其血压、肾脏尿钠排泄功能、D3 受体的蛋白/mRNA、血浆肾素活性、去甲肾上腺素的浓度、血管紧张素Ⅱ1型（AT1）受体的表达进行测定;并通过离体肠系膜动脉孵育,研究刺激D3 受体对血管舒缩功能的影响.结果无论收缩压或舒张压,D3-/-小鼠均明显高于野生型（D3＋/＋）小鼠.给予盐负荷后,2组小鼠血压均无明显变化,然而在盐负荷后最后1个时间段的尿钠排泄量,D3-/-小鼠低于D3＋/＋小鼠.分析肾脏肾素活性和AT1受体的表达发现D3-/-小鼠高于D3＋/＋小鼠.2组小鼠肾脏中去甲肾上腺素的水平无区别.AT1受体拮抗剂的降血压作用D3-/-小鼠明显且持久.离体肠系膜动脉研究发现刺激D3受体可舒张动脉血管.结论 D3-/-小鼠的血压升高除与肾脏的尿钠排泄功能下降有关,还与D3受体介导的舒血管功能障碍有关.     

多巴胺D_5受体在血压调控中的作用

交感神经系统在高血压(EH)发生、发展中的作用已得到人们的公认,儿茶酚胺是交感神经发挥作用的神经递质,它包括肾上腺素(E)、去甲肾上腺素(NE)和多巴胺,既往的研究显示多巴胺具有与ENE相反的作用,在交感神经系统兴奋的同时,多巴胺可以通过其受体发挥对机体的保护作用。刺激多巴胺受体具有扩张血管、利尿排钠、调节肾脏和血管氧化应激状态的作用,从而对血压的调控发挥一定的作用[1-3]。多巴胺受体分为D1类、D2类两个亚家族;D1类受体(包括D1、D5)与刺激型G蛋白(GαsGolf)耦联,刺激腺苷酸环化酶的活性。D2类受体包括D2、D3、D4亚型,与…     

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Essential hypertension has a heritability as high as 30-50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D(1)-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D(1) dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4gamma, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D(1) receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4gammaA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D(1)-like agonist stimulation. These findings provide a mechanism for the D(1) receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.     

肾脏内皮素B受体参与D_3受体介导WKY大鼠尿钠排泄调节

目的肾脏多巴胺和内皮素(ET)系统通过影响近曲小管尿钠排泄在血压调节中发挥重要作用。敲除 ETB 受体基因或 D_3多巴胺受体基因均形成盐敏感性高血压小鼠,并伴有尿钠排泄能力降低;本试验将探索D_3受体和 ETB 受体之间是否存在相互作用以及该作用对 WKY 大鼠尿钠排泄的影响。方法应用 D_3受体激动剂、拮抗剂和 ETB 受体拮抗剂灌注 WKY 大鼠右肾动脉,观察刺激、抑制 D_3、ETB 受体后 WKY 肾功能尤其是尿钠排泄的变化。结果 PD128907刺激 D_3受体后,WKY 尿钠排泄增加,PD128907介导的促尿钠排泄作用可被 D_3受体拮抗剂 GR103691所阻断;ETB 受体拮抗剂 BQ788本身对尿钠排泄无明显影响,但可部分阻断 D_3受体介导的利钠作用。结论 D_3受体的促尿钠排泄作用部分通过 ETB 受体完成。     

G蛋白激酶4γA142V转基因小鼠血压升高的机制探讨

目的探讨G蛋白激酶(GRK)4γ变异体A142V转基因小鼠血压升高的原因,以期了解GRK4γ在调控血压中的作用。方法以GRK4γA142V转基因小鼠为研究对象,分别对其血压、肾脏尿钠排泄功能、D1多巴胺受体的表达进行测定;并应用GRK4反义核苷酸技术处理HK-2细胞,研究在GRK4表达受到抑制的情况下D1受体的表达变化。结果与对照小鼠相比,GRK4γA142V转基因小鼠血压明显增高,肾脏D1受体介导的利尿、利钠作用明显下降,伴有肾脏皮质膜D1受体表达降低(0.6±0.2比1.5±0.2,n=3)、磷酸化程度增高[(65±7)DU比(35±7)DU,n=3];反义核苷酸抑制GRK4(1.2±0.1比1.3±0.1比0.6±0.1,n=6)表达后,D1受体的表达量增高(0.7±0.1比0.8±0.1比1.5±0.2,n=6),说明D1受体功能下降是GRK4γA142V转基因小鼠血压升高的原因。结论GRK4γ与高血压的发生关系密切,GRK4γA142V转基因小鼠血压升高与肾脏D1受体功能下降有关。     

多巴胺D_1类受体对血管平滑肌细胞胰岛素样生长因子1受体表达的影响

目的观察多巴胺 D_1类受体对血管平滑肌细胞胰岛素样生长因子1(IGF-1)受体的影响。方法以A10细胞为研究对象,免疫印迹观察刺激 D_1类受体对 IGF-1受体表达的影响,并初步探讨 D_1类受体对 IGF-1受体影响的机制。结果刺激 D_1类受体可降低 IGF-1受体的表达,D_1类受体阻断剂可完全阻断 D_1类受体激动剂Fenoldopam 对 IGF-1受体的影响,免疫印迹显示运用蛋白激酶 C(PKC)和促分裂原活化蛋白激酶(MAPK)阻断剂后,IGF-1受体表达恢复,提示 PKC 和 MAPK 途径可能参与了 D_1类受体对血管平滑肌细胞 IGF-1受体的影响过程,在 Wistar-Kyoto(WKY)大鼠和自发性高血压大鼠(SHR)血管平滑肌细胞中 D_1类受体激动剂 Fenoldopam 对IGF-1受体表达具有抑制作用,但该抑制作用在 SHR 细胞明显低于 WKY 细胞。结论 D_1类受体对血管平滑肌细胞 IGF-1受体表达具有抑制作用,该作用可能通过 PKC 和 MAPK 途径发挥一系列生理效应。     

Reactive Oxygen Species and Dopamine Receptor Function in Essential Hypertension

Essential hypertension is a major risk factor for stroke, myocardial infarction, and heart and kidney failure. Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones and humoral factors. However, the mechanisms leading to impaired dopamine receptor function in hypertension states are not clear. Compelling experimental evidence indicates a role of reactive oxygen species (ROS) in hypertension, and there are increasing pieces of evidence showing that in conditions associated with oxidative stress, which is present in hypertensive states, dopamine receptor effects, such as natriuresis, diuresis, and vasodilation, are impaired. The goal of this review is to present experimental evidence that has led to the conclusion that decreased dopamine receptor function increases ROS activity and vice versa. Decreased dopamine receptor function and increased ROS production, working in concert or independent of each other, contribute to the pathogenesis of essential hypertension.     

Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression

Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.     

Dopamine receptors and hypertension

Dopamine plays an important role in regulating renal function and blood pressure. Dopamine synthesis and dopamine receptor subtypes have been shown in the kidney. Dopamine acts via cell surface receptors coupled to G proteins; the receptors are classified via pharmacologic and molecular cloning studies into two families, D₁-like and D₂-like. Two D₁-like receptors cloned in mammals, the D1 and D5 receptors (D1A and D1B in rodents), are linked to adenylyl cyclase stimulation. Three D₂-like receptors (D2, D3, and D4) have been cloned and are linked mainly to adenylyl cyclase inhibition. Activation of D₁-like receptors on the proximal tubules inhibits tubular sodium reabsorption by inhibiting Na/H-exchanger and Na/K-adenosine triphosphatase activity. Reports exist of defective renal dopamine production and/or dopamine receptor function in human primary hypertension and in genetic models of animal hypertension. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to hypertension. A primary defect in D₁-like receptors and an altered signaling system in proximal tubules may reduce dopamine-mediated effects on renal sodium excretion. The molecular basis for dopamine receptor dysfunction in hypertension is being investigated, and may involve an abnormal posttranslational modification of the dopamine receptor.     

内皮素B受体对自发性高血压大鼠肾脏近曲小管上皮细胞多巴胺D_3受体的异常调节

目的探讨内皮素 B(ETB)受体对肾脏近曲小管上皮细胞多巴胺 D_3受体表达的影响,以及其与高血压(EH)发生之间的关系。方法以 Wistar-Kyoto(WKY)大鼠和自发性高血压大鼠(SHR)肾脏近曲小管上皮细胞(RPT)株为研究对象,观察刺激 ETB 受体后 D_3受体蛋白表达的变化,D_3受体的蛋白表达采用免疫印迹测定,ETB/D_3受体之间的连接采用免疫沉淀测定。结果 ETB 受体激动剂 BQ3020可增加 WKY 大鼠 RPT 细胞 D_3受体的蛋白表达,该作用呈现出时间依赖性和剂量依赖性关系,而且 BQ3020对 D_3受体蛋白表达的刺激作用可以被D_3受体拮抗剂 BQ788所抑制。在 SHR 细胞,ETB 受体激动剂 BQ3020并不能增加 RPT 细胞 D_3受体的蛋白表达,并且基础状态下 D_3受体的蛋白表达在 SHR 细胞明显低于 WKY 细胞。免疫共沉淀显示在 ETB/D_3受体之间存在同连接,刺激 ETB 受体可增加 ETB/D_3受体之间的连接程度,然而,在 SHR 细胞,不仅基础状态下 ETB/D_3受体之间的连接程度低,而且,刺激 ETB 受体对 ETB/D_3受体之间的连接程...     

Decreased Urinary Dopamine Excretion and Disturbed Dopamine/Sodium Relationship in Type 1 Diabetes Mellitus

In Type 1 diabetes an increased total body sodium and an impaired ability to excrete a sodium load have been described. A possible involvement of the renal dopaminergic system in this abnormal sodium handling was evaluated through measurements of the urinary output of dopamine, sodium, the dopamine/sodium correlation, and through examining the effect of a dopamine infusion on urinary sodium excretion. Twenty-four hour urinary dopamine excretion was significantly lower in Type 1 diabetic patients as compared to normal controls. A significant correlation between urinary dopamine and sodium excretion was present in normoalbuminuric Type 1 diabetic patients and in normal controls. However, no such correlation could be found in microalbuminuric patients. The increase in fractional excretion of sodium during a 1 h low-dose dopamine (3 μg kg^?1min^?1) infusion in Type 1 diabetic patients was negatively correlated with diabetes duration. Patients with short duration of diabetes (less than 15 years) had a comparable dopamine-induced increase in fractional excretion of sodium as normal controls. However, patients with longer duration of diabetes (more than 15 years) and microalbuminuric patients displayed no significant changes in sodium output during dopamine infusion. These findings suggest that in Type 1 diabetes mellitus a deficiency of renal dopamine production could be responsible for the impaired sodium handling. Longer duration of the disease and microalbuminuria seem to be associated with an uncoupling of the urinary dopamine/sodium relationship.