SODIUM PUMP INHIBITORS IN BLOOD PRESSURE REGULATION

钠泵抑制剂在血压调节中的作用

• 批准号: 6097847
• 负责人: Olga V Fedorova
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6097847
• 关键词: adrenocorticotropic hormone; blood pressure; cardiovascular pharmacology; dietary sodium; digitalis; enzyme inhibitors; hemodynamics; laboratory rat; nutrition related tag; ouabain; sodium potassium exchanging ATPase

SUMMARY OF WORK Many factors involved in the pathogenesis of NaCl sensitive hypertension remain to be clarified, including mechanisms of dysregulation of the Na/K pump (NKP). Previous studies in our laboratory have shown that two endogenous ligands of Na/K ATPase (NKA), ouabain-like factor (OLC) and marinobufagenin (MBG) exhibit vasoconstrictor activity, and are responsive to saline loading and plasma volume expansion (VE). At the same time, OLC and MBG differ with respect to effective stimuli to increase and their time courses, and their targets ( -3 and -1 isoforms of the sodium pump). During the current year we have completed two projects studying digitalis-like factors (DLF) in rats, during acute VE, and during a combination of high salt intake and isolation stress. In VE, OLC increased in the pituitary, while MBG rose in plasma. In the second, chronic experiment, in rats exposed to isolation stress, the excretion of OLC but not MBG was stimulated. Conversely, plasma MBG, but not OLC was responsive to a high NaCl diet. Both procedures alone did not affect the blood pressure (BP). At the same time, the combination of high NaCl diet with isolation stress resulted in an initial response of OLC followed by a progressive increase in MBG excretion, which paralleled an increase in BP. The studies of combined action of DLFs were continued in Dahl hypertension, which resembles salt hypertension in humans in many aspects. The first experiment showed that acute salt loading of both Dahl salt-sensitive (DS) and salt-resistant (DR) rats elicited similar DLF responses in both strains: an acute rise in OLC excretion followed by a slower rise in MBG, which paralleled the BP increase. However, chronic exposure of DS and DR to 4% and 8% NaCl diet revealed differences in the DLF responses: in DS, an initial transient rise of OLC was followed by a delayed but sustained rise in MBG, which paralleled a dramatic hypertensive response. No such DLF responses were observed in DR. In another study, in human mesenteric arteries, we have shown that distribution of NKA isoforms was different from that in rat vessels, both -1 and -3 subunit were present in sarcolemma and in nerve endings membranes. At nanomolar concentrations, MBG and OLC interacted with nerve endings NKA causing an apparent stimulation of NKP by norepinephrine, which overshadowed the inhibition of sarcolemmal NKP.Clinical studies have demonstrated increased plasma levels of MBG in volume-expanded states, such as essential hypertension, renal failure, and preeclampsia. Data on further characterization of plasma bufodienolide DLF are consistent with our previous results obtained with the urinary inhibitor.

工作总结涉及多个因素 盐敏感型高血压的发病机制尚不清楚 阐明，包括钠/钾泵调节失调的机制 (NKP)。我们实验室以前的研究表明，有两个 哇巴因样因子Na/K-ATPase内源性配体(NKA) (OLC)和Marinobufagenin(MBG)表现为血管收缩 活性，并对生理盐水负荷和血浆容量做出反应 扩展(VE)。同时，OLC和MBG与 关于有效刺激增加及其时间进程，以及 它们的靶标(钠泵的-3和-1亚型)。在.期间 今年我们已经完成了两个研究洋地黄类物质的项目 大鼠的因子(DLF)，在急性VE期间和在 高盐摄入量和隔离应激。在VE中，OLC在 脑垂体，而血浆中MBG升高。第二种是慢性病 实验中，在暴露于隔离应激的大鼠中， 刺激OLC，但不刺激MBG。相反，血浆MBG，但 Not OLC对高盐饮食有反应。这两种程序 单独使用不会影响血压(BP)。同时， 高盐饮食和隔离应激相结合导致了 OLC的初步反应，随后MBG逐渐增加 排泄物，这与BP的增加是平行的。的研究 在Dahl高血压患者中，DFL的联合作用继续存在， 这在许多方面与人类的盐分高血压相似。这个 第一次实验表明，急性盐负荷的两个Dahl 盐敏感(DS)和耐盐(DR)大鼠产生类似的DLF 两种菌株的反应：OLC排泄量随后急剧上升 MBG上升较慢，这与BP的上升平行。 然而，DS和DR长期暴露在4%和8%的食盐饮食中 揭示了DLF反应的差异：在DS中，初始瞬变 OLC上升之后，MBG出现了延迟但持续的上升， 这与戏剧性的高血压反应是平行的。没有这样的DLF 在另一项研究中，博士观察到了反应，在人类 肠系膜动脉，我们已经显示了NKA的分布 异构体与大鼠血管中的不同，-1和-3 亚基存在于肌膜和神经末梢中。 膜。在纳摩尔浓度下，MBG和OLC 与神经末梢NKA相互作用产生明显的刺激 去甲肾上腺素对NKP的抑制作用 肌膜NKP临床研究显示增加 容量扩张状态下的血浆MBG水平，如必需的 高血压、肾功能衰竭和先兆子痫。有关进一步发展的数据 蟾酥二烯内酯DLF的血浆特征与 我们之前的研究结果是通过尿液抑制剂获得的。