Sodium Pump Inhibitors In Blood Pressure Regulation

盐敏感性高血压占全球高血压患者的40%。尽管如此，盐敏感性的分子机制还没有得到很好的理解。一种理论认为内源性CTS在盐敏感性高血压的发病机制中起核心作用。两种CTS，内源性哇巴因和MBG，共存于哺乳动物组织中。MBG作为NKA的哇巴因抗性α-1同种型的选择性抑制剂，NKA是肾脏、血管平滑肌和成体心肌细胞中的主要同种型。在Dahl盐敏感大鼠（DS）中，高NaCl摄入量，脑内源性哇巴因触发外周MBG，从而升高BP。在人类中，中等NaCl负荷导致MBG产生增加。 为了确定CTS、高NaCl摄入、BP和利钠功能之间的关系，我们与David E.安德森和奥勒·梅兰德。 SALT研究的结果表明，在绝经后妇女中，MBG与肾钠排泄有关，并表明随着年龄的增加，随着NaCl负荷的增加，尿钠排泄MBG水平的增加相对失败，可能是随着年龄的增长，血压对NaCl的敏感性增加的一个因素。由于本研究中的受试者血压正常，我们的研究结果并不一定反映盐敏感性或NaCl诱导的MBG生产高血压患者。 在SARAH研究中，39例受试者（20例男性和19例女性; 53 - 11岁）在基线条件下接受检查（NaCl摄入量未标准化），此后在提供的膳食和饮料中接受50 mmol NaCl/天，持续8周。此外，NaCl胶囊（100 mmol/天）和相应的安慰剂胶囊以随机顺序给药4周。在基线、50 mmol/d（低盐，LS）4周后和150 mmol/d（高盐，HS）4周后测量MBG和24小时动态BP。 从LS到HS的饮食盐的转变引起两种性别的SBP和DBP升高，并与血浆MBG增加相关。与SALT研究相似，HS时血浆MBG与两种性别的肾钠排泄呈正相关。与SALT相反，在SARAH中，两种性别的肾脏MBG排泄与SBP均未表现出负相关性。然而，如在SALT研究中观察到的，女性的SBP水平与肾钠排泄呈负相关，但在男性受试者中不相关。女性而非男性的SBP变化与年龄呈临界显著正相关（与SALT研究相似）。在> 45岁的女性中，这种相关性变得很强且显著（R =-0.66，P =0.01）。在两种性别中，HS上的肾MBG排泄与年龄呈负相关，如在SALT研究中，但男性中LS至HS的MBG排泄（HS上的MBG与LS上的MBG之比）增加了一倍，但女性中没有，与年龄呈强正相关。在男性中，而不是在女性中，基线血浆MBG与HS时的24小时DBP直接相关。 两项研究的数据表明，MBG是BP盐敏感性的重要决定因素，其对盐的反应及其与BP盐敏感性的关系因年龄和性别而异。而在老年女性中，MBG产生的相对失败可能导致体积膨胀并导致高血压，在男性中，衰老与较低的基线MBG水平相关，但MBG对HS的反应性更高。值得注意的是，在衰老的雄性Sprague-Dawley大鼠中也发现了类似的关系。

Salt-sensitive hypertension accounts for 40% of the hypertensives worldwide. Still, molecular mechanisms of salt-sensitivity are not well understood. One theory attributes endogenous CTS a central role in the pathogenesis of salt-sensitive hypertension. Two CTS, endogenous ouabain and MBG, coexist in mammalian tissues. MBG acts as a selective inhibitor of ouabain-resistant alpha-1 isoform of NKA, the main isoform in the kidney, vascular smooth muscle and adult cardiomyocytes. In Dahl salt-sensitive rats (DS) on a high NaCl intake, brain endogenous ouabain triggers peripheral MBG, which raises the BP. In humans, moderate NaCl-loading causes increase in MBG production. In order to define the relationships between CTS, high NaCl intake, BP and natriuretic function, we analyzed levels of endogenous ouabain and MBG in two human studies, SALT (NIA), and SARAH (Lund University, Malmo, Sweden) in collaboration with Drs. David E. Anderson and Olle Melander. The results of SALT study demonstrate that in post-menopausal women, MBG is implicated in renal sodium excretion, and suggest that a relative failure to increase natriuretic MBG levels in response to NaCl-loading with increasing age could be a factor in the increase in NaCl sensitivity of BP with aging. Because subjects in the present study were normotensive, our findings do not necessarily reflect salt sensitivity or NaCl-induced MBG production in hypertensive patients. In the SARAH study, 39 subjects (20 males and 19 females; 5311 years) were examined under baseline conditions (NaCl-intake not standardized) and thereafter received 50 mmol NaCl/day for 8 weeks in provided meals and drinks. In addition, NaCl capsules (100 mmol/day) and corresponding placebo capsules were administered for 4 weeks each in random order. MBG and 24-hour ambulatory BP were measured at baseline, after 4 weeks of 50 mmol/day (low salt, LS) and after 4 weeks of 150 mmol/day (high salt, HS). The shift in dietary salt from LS to HS caused elevations of SBP and DBP in both genders and was associated with an increase in plasma MBG. Similar to that in SALT study, plasma MBG at HS positively correlated with renal sodium excretion in both genders. In contrast to SALT, in SARAH, in both genders renal MBG excretion did not exhibit negative correlation with SBP. Levels of SBP, however, negatively correlated with renal sodium excretion in females, as observed in SALT study, but not in male subjects. Changes in SBP in females, but not in males exhibited a borderline significant positive correlation with age (like in SALT study). In females > 45 years old this correlation became strong and significant (R= -0.66, P=0.01). In both sexes renal MBG excretion on HS negatively correlated with age, as in SALT study, but a fold of increase of MBG excretion from LS to HS (ratio of MBG on HS to MBG on LS) in males, but not in females, exhibited a strong positive correlation with age. In males, but not in females, baseline plasma MBG was directly related to 24h DBP on HS. Data from both studies suggest that MBG is an important determinant of salt-sensitivity of BP and that its reaction to salt and its relation to salt sensitivity of BP differs by age and gender. While in older females, a relative failure in MBG production may cause volume expansion and contribute to hypertension, in males, aging is associated with lower baseline MBG levels, but a greater responsiveness of MBG to HS. Note that a similar relationship was found in aging male Sprague-Dawley rats.