SODIUM PUMP INHIBITORS IN BLOOD PRESSURE REGULATION

涉及的许多因素 氯化钠敏感性高血压发病机制尚不清楚， 澄清，包括钠/钾泵失调的机制 （NKP）。我们实验室以前的研究表明， Na/K ATP酶（NKA）、哇巴因样因子的内源性配体 (OLC)和海蟾毒配基（MBG）显示血管收缩作用， 活性，并对生理盐水负荷和血浆容量有反应 扩展（VE）。同时，OLC和MBG与 关于增加的有效刺激及其时间进程，以及 它们的目标（钠泵的-3和-1亚型）。期间 今年，我们完成了两个研究数字化的项目， 在急性VE期间，以及在 高盐摄入和隔离压力。在VE中，OLC在 血浆MBG含量升高。第二，慢性 实验，在大鼠暴露于隔离应激，排泄的 刺激OLC，但不刺激MBG。相反，血浆MBG，但 而OLC对高NaCl饮食无反应。两种程序 单独使用不影响血压（BP）。同时对 高盐饮食与隔离胁迫的组合导致了 OLC的初始反应，随后MBG逐渐增加 排泄，这会导致血压升高。的研究 Dahl型高血压患者DLF的联合作用持续， 其在许多方面类似于人类的盐性高血压。的 第一个实验表明，急性盐负荷的达尔 盐敏感（DS）和盐耐受（DR）大鼠诱发的DLF相似 两种菌株的反应：OLC排泄急剧上升， MBG的缓慢上升，抑制了BP的上升。 然而，DS和DR慢性暴露于4%和8%NaCl饮食， 揭示了DLF反应的差异：在DS中，初始瞬态 OLC上升之后是MBG延迟但持续的上升， 这意味着剧烈的高血压反应。无此类DLF 在DR中观察到反应。在另一项研究中， 肠系膜动脉，我们已经显示了NKA的分布， 与大鼠血管中的同种型不同，均为-1和-3 亚单位存在于肌膜和神经末梢中 膜。在纳摩尔浓度，MBG和OLC 与神经末梢NKA相互作用，引起明显的刺激 NKP的去甲肾上腺素，这掩盖了抑制 肌膜NKP。临床研究表明， 血浆MBG水平在体积膨胀状态，如必要的 高血压肾衰竭和先兆子痫数据进一步 血浆蟾毒双烯内酯DLF的表征与 我们以前用尿抑制剂得到的结果。

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.