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...     

多巴胺D3受体对SHR大鼠肾脏内皮素B受体的异常调节在高血压发生中的作用

目的 探讨多巴胺D3受体对肾脏内皮素B(ETB)受体表达及功能的调节与高血压(EH)发生的关系.方法 分别以D3多巴胺受体基因敲除(D3-/-)小鼠和肾脏近曲小管上皮细胞(RPT)株为研究对象,观察刺激D3受体后ETB受体蛋白表达和功能的变化,D3受体的蛋白表达采用免疫印迹测定,ETB受体的功能采用Na -K -ATP酶活性表示.结果 D3-/-小鼠肾脏皮质ETB受体的蛋白表达(0.8±0.2)DU明显低于对照小鼠[(1.2±0.1)DU,P＜0.05,n=5];D3受体兴奋剂PD128907(10-7 mol/L·24 h)刺激D3受体可增加Wistar-Kyoto(WKY)大鼠RPT细胞ETB受体的表达,却抑制自发性高血压(SHR)大鼠ETB受体的表达[WKY:(对照1.0±0.1比PD128907:1.5±0.1)DU;SHR:(对照:1.0±0.1比PD128907:0.7±0.2)DU;n=9,P＜0.05].用ETB受体激动剂BQ3020(10-8 mol/L·15 min)刺激ETB受体可明显降低WKY大鼠RPT细胞的Na -K -ATP酶的活性,但在SHR的RPT细胞,这种抑制作用却丧失;基础状态下SHR的Na -K -ATP酶活性明显高于WKY大鼠.预先刺激D3受体均可使ETB受体对Na -K -ATP酶活性的抑制作用进一步加强,但这种作用在WKY的RPT细胞明显强于SHR的RPT细胞(下降幅度SHR:9.1%比WKY:16.9%).结论 D3受体通过对ETB受体蛋白表达的调节作用,从而调控ETB受体的功能,D3/ETB受体之间的异常调节参与了EH发生的发病机制.     

多巴胺D_3受体对SHR大鼠肾脏内皮素B受体的异常调节在高血压发生中的作用

目的探讨多巴胺D3受体对肾脏内皮素B(ETB)受体表达及功能的调节与高血压(EH)发生的关系。方法分别以D3多巴胺受体基因敲除(D3-/-)小鼠和肾脏近曲小管上皮细胞(RPT)株为研究对象,观察刺激D3受体后ETB受体蛋白表达和功能的变化,D3受体的蛋白表达采用免疫印迹测定,ETB受体的功能采用Na -K -ATP酶活性表示。结果D3-/-小鼠肾脏皮质ETB受体的蛋白表达(0·8±0·2)DU明显低于对照小鼠[(1·2±0·1)DU,P<0·05,n=5];D3受体兴奋剂PD128907(10-7mol/L·24h)刺激D3受体可增加Wistar-Kyoto(WKY)大鼠RPT细胞ETB受体的表达,却抑制自发性高血压(SHR)大鼠ETB受体的表达[WKY(对照1·0±0·1比PD1289071·5±0·1)DU;SHR(对照1·0±0·1比PD1289070·7±0·2)DU;n=9,P<0·05]。用ETB受体激动剂BQ3020(10-8mol/L·15min)刺激ETB受体可明显降低WKY大鼠RPT细胞的Na -K -ATP酶的活性,但在SHR的RPT细胞,这种抑制作用却丧失;基础状态下SHR的Na -K -ATP酶活性明显高于WKY大鼠。预先刺激D3受体均可使ETB受体对Na -K -ATP酶活性的抑制作用进一步加强,但这种作用在WKY的RPT细胞明显强于SHR的RPT细胞(下降幅度SHR9·1%比WKY16·9%)。结论D3受体通过对ETB受体蛋白表达的调节作用,从而调控ETB受体的功能,D3/ETB受体之间的异常调节参与了EH发生的发病机制。     

内皮素B受体对肾近曲小管上皮细胞Na+-K+-ATP酶活性的影响

目的 探讨内皮素B(ETB)受体对肾脏近曲小管(RPT)上皮细胞Na -K -ATP酶活性的影响和机制.方法 以WKY(Wistar-Kyoto)大鼠RPT细胞为研究对象,Na -K -ATP酶活性采用哇巴因法进行测定.结果 ETB受体激动剂BQ3020能明显降低Na -K -ATP酶的活性,这一抑制作用呈浓度和时间依赖性,BQ3020 10-8 mol/L刺激15 min达最大效应,下降幅度达36.1%;用细胞膜钙通道阻断剂尼卡地平预先刺激细胞后,能够阻断ETB受体对Na -K -ATP酶的抑制效应;在无钙状态下,ETB受体激动剂BQ3020对Na -K -ATP酶的抑制效应丧失.结论 ETB受体在RPT处通过降低Na -K -ATP酶活性调节离子转运;细胞外钙内流参与了ETB受体对Na -K -ATP酶活性抑制作用的信号途径.     

内皮素B受体对肾近曲小管上皮细胞Na~ -K~ -ATP酶活性的影响

目的探讨内皮素B(ETB)受体对肾脏近曲小管(RPT)上皮细胞Na -K -ATP酶活性的影响和机制。方法以WKY(Wistar-Kyoto)大鼠RPT细胞为研究对象,Na -K -ATP酶活性采用哇巴因法进行测定。结果ETB受体激动剂BQ3020能明显降低Na -K -ATP酶的活性,这一抑制作用呈浓度和时间依赖性,BQ302010-8mol/L刺激15min达最大效应,下降幅度达36.1%;用细胞膜钙通道阻断剂尼卡地平预先刺激细胞后,能够阻断ETB受体对Na -K -ATP酶的抑制效应;在无钙状态下,ETB受体激动剂BQ3020对Na -K -ATP酶的抑制效应丧失。结论ETB受体在RPT处通过降低Na -K -ATP酶活性调节离子转运;细胞外钙内流参与了ETB受体对Na -K -ATP酶活性抑制作用的信号途径。     

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.     

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.     

胰岛素对肾脏近曲小管上皮细胞多巴胺D5受体表达和功能的影响

目的 观察胰岛素对肾脏近曲小管上皮(RPT)细胞多巴胺D5受体表达与功能的影响.方法 以RPT细胞与多巴胺D5受体转染的HEK293(HEK-D5)细胞为研究对象,观察胰岛素对D5受体表达与功能的影响,并在Wistar-Kyoto(WKY)大鼠与自发性高血压大鼠(SHR)的RPT细胞上比较这种影响的区别.观察在胰岛素[10-7 mmol/(L·24 h)]预先作用与否的情况下,D5受体(D1 类激动剂 Fenoldopam)对Na -K -ATP 酶活性的影响.结果 胰岛素可升高WKY的RPT细胞D5受体表达,该作用呈现作用浓度与时间依赖性;在SHR的RPT细胞却出现截然不同的现象,刺激胰岛素受体却降低了D5受体的表达;基础状态下,SHR的RPT细胞D5受体的表达明显低于WKY细胞.与单用Fenoldopam相比,在胰岛素(10-7 mmol/L/24 h)预先刺激的情况下,Fenoldopam降低Na -K -ATP酶的作用增强.结论 胰岛素可调节RPT细胞D5的表达和功能,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。     

高血压发生中多巴胺D4受体对肾脏近曲小管细胞血管紧张素Ⅱ1型受体的异常调控

目的 研究多巴胺D4受体对肾脏近曲小管上皮(RPT)细胞上血管紧张素Ⅱ 1型受体(AT1R)表达的异常调控在原发性高血压(EH)发生中的作用.方法 以Wistar-Kyoto(WKY)大鼠的RPT细胞株作为研究对象,采用免疫印迹法测定刺激D4受体后AT1R的表达变化,并观察其作用机制及信号途径.结果 D4受体激动剂PD168077(10-64mol/L,24 h)刺激D4受体可明显抑制WKY大鼠RPT细胞AT1R的表达,该作用呈现浓度和时间依赖性关系;PD168077对AT1R表达的抑制作用可被D4受体特异性阻断剂L745870(10-6mol/L)所阻断;相反,在EH状态下这种作用受损,PD168077反而增加AT1R的表达.在钙通道拮抗剂尼卡地平存在的情况下D4受体对WKY细胞AT1R的抑制作用被阻断,提示D4受体对AT1R的下调作用可能通过钙通道途径发生影响.结论 D4受体对AT1R蛋白表达具有抑制作用,该作用受损可能在高血压的发生、发展过程中发挥一定作用.     

Peptide Receptor Imaging

Radiolabeled cell-surface peptide receptor-binding molecules are emerging as an important class of radiopharmaceuticals. Their binding to specific cell membrane receptors allows for noninvasive assessment of regional receptor proteomics in vivo. Information thus obtained can be used for diagnostic purposes and for predicting and monitoring response to treatment. This paradigm also applies to pulmonary diseases. In this review, available radiopharmaceuticals of great potential or already in clinical use for imaging of lung cancer, lung inflammation and infection and pulmonary embolism are discussed.In lung cancer, somatostatin receptor imaging by means of technetium-99m (^99mTc)-octreotide scintigraphy has proven useful for characterizing malignancy in solitary pulmonary nodules. Additionally, several radiopharmaceuticals targeting tyrosine-kinase, e.g. ^99mTc labeled epidermal growth factor and indium-111 (¹¹¹In)-diethylene triamine penta-acetic acid-trastuzumab, or G-protein coupled receptors, e.g. ^99mTc-bombesin, iodine-123-vasoactive intestinal peptide and ¹¹¹In-tetraazacyclododecane tetra-acetic acid (DOTA)-cholecystokinine-B, are being explored for their diagnostic as well as treatment monitoring potential.With the purpose of better evaluating the source of pulmonary embolism, as well as to differentiate acute from chronic deep venous thrombosis, several radiolabeled peptides targeting the glycoprotein IIb/IIIa fibrinogen receptor found on activated platelets have been developed. Out of these, ^99mTc-P280 is now approved by the US Food and Drug Administration for scintigraphic imaging of suspected acute venous thrombosis in the lower extremities of patients.In the field of lung inflammation and infection, non-specific ¹¹¹In and ^99mTc-human polyclonal immunoglobulins have been successfully used to identify the presence and extent of Pneumocystis carinii, cytomegalovirus, Mycobaterium avium and fungal infections in patients with HIV infection. The clinical role of other radiopharmaceuticals such as ^99mTc-J001X, a nonpyrogenic acylated polygalactoside isolated from Klebsiella pneumoniae and binding with high affinity to CD11b and CD14 lipopolysaccharide receptors expressed on monocytes/macrophages, and ¹¹¹In-octreotide, binding to up-regulated somatostatin receptors on activated lymphocytes needs to be further defined.     

Gastrin Receptor Pharmacology

C-terminally amidated gastrins act at cholecystokinin-2 receptors (CCK2R), which are normally expressed by gastric parietal and enterochromaffin-like (ECL) cells and smooth muscle; there is also extensive expression in the CNS where the main endogenous ligand is cholecystokinin. A variety of neoplasms express CCK2R, or splice variants, including neuroendocrine, pancreatic, medullary thyroid and lung cancers. Other products of the gastrin gene (progastrin, the Gly-gastrins) may stimulate cell proliferation but are not CCK2R ligands. Depending on the cell type, stimulation of CCK2R evokes secretion, increases proliferation and cell migration, inhibits apoptosis, and controls the expression of various genes. These effects are mediated by increased intracellular calcium and activation of protein kinase C, MAPkinase and other protein kinase cascades. There has been recent progress in developing CCK2R ligands that can be used for imaging tumours expressing the receptor. New antagonists have also been developed, and there is scope for using these for suppression of gastric acid and for treatment of neuroendocrine and other CCK2R-expressing tumours.     

Anti-N-Methyl-d-Aspartate Receptor Encephalitis

A case of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis with an atypical finding of transient increased intracranial pressure is reported. Anti-NMDAR encephalitis is an underrecognized, novel and treatable form of encephalitis being increasingly identified as an explanation of encephalitis in young adults. Management of these patients requires a multidisciplinary approach involving neurologists, internists, nursing and rehabilitation staff. It is important for internists to recognize this condition and consider it in the differential diagnosis of encephalopathy. Internists also need to be familiar with the clinical manifestations and the treatment of the disease as they have an important role in the care of these patients during their prolonged stay in the hospital. Increased intracranial pressure is an atypical and underrecognized finding that has been only noted in a previous review on this disorder. It may present a diagnostic or management challenge in patients with anti-NMDAR encephalitis.     

Endocannabinoid Receptor Antagonists

Obesity has been described as a global epidemic. Its increasing prevalence is matched by growing costs, not only to the health of the individual, but also to the medical services required to treat a range of obesity-related diseases. In most instances, obesity is a product of progressively less energetic lifestyles and the over-consumption of readily available, palatable, and highly caloric foods. Past decades have seen massive investment in the search for effective anti-obesity therapies, so far with limited success. An important part of the process of developing new pharmacologic treatments for obesity lies in improving our understanding of the psychologic and physiologic processes that govern appetite and bodyweight regulation. Recent discoveries concerning the endogenous cannabinoids are beginning to give greater insight into these processes. Current research indicates that endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possibly mediating the craving for and enjoyment of the most desired, most fattening foods. Additionally, endocannabinoids appear to modulate central and peripheral processes associated with fat and glucose metabolism. Selective cannabinoid receptor antagonists have been shown to suppress the motivation to eat, and preferentially reduce the consumption of palatable, energy-dense foods. Additionally, these agents act to reduce adiposity through metabolic mechanisms that are independent of changes in food intake. Given the current state of evidence, we conclude that the endocannabinoids represent an exciting target for new anti-obesity therapies.     

血管紧张素1型受体和2型受体的交互作用

血管紧张素Ⅱ (AngⅡ )主要作用于血管紧张素 1型受体和 2型受体 (AT1、AT2 )而发挥作用 ,AngⅡ与受体间的复杂相互作用在其生理效应的发挥中担当重要角色。本文重点讨论AT1与AT2 间的交互作用及与缓激肽 /NO/cGMP之间的关系 ,有助于对肾素 血管紧张素系统 (RSA)病理生理机制的理解及拮抗RAS疗法新策略的发展。     

瞬时受体电位香草酸亚型1在心血管系统中的调节作用

瞬时受体电位香草酸亚型1属于瞬时受体电位通道家族,可被辣椒素激活,在全身多处器官组织表达。主要通过调节细胞内Ca2+离子浓度,从而发挥多功能细胞感受器功能。该篇综述主要介绍目前瞬时受体电位香草酸亚型1在心血管系统中的功能研究,主要表现在调节血管张力,高血压发生、心肌缺血中的保护作用及预防动脉粥样硬化、植物神经功能影响几个方面,有望为心血管疾病诊治提供新的靶点。