Aging and interaction of natriuretic factors on renal and vascular sodium pump

在第一项临床研究中，39名健康受试者（53 +/-11岁; 20名男性和19名女性）每日总NaCl摄入量为50 mmol（低盐）和150 mmol（高盐），各持续4周，随机顺序。在基线（非标准化盐摄入）和高盐和低盐摄入后测量血浆中的动脉血压和MBG水平。基线时血浆MBG（P-MBG）与24小时收缩压（r = 0.43，P = 0.007）和舒张压（r = 0.32，P = 0.047）相关。有趣的是，性别特异性分析显示，这些关系仅在男性中显着。与低盐相比，高盐饮食增加了P-MBG（P = 0.029），主要是由男性的结果驱动的。男性P-MBG应答者，在低盐和高盐摄入之间表现出最大的Δ P-MBG，（10.4 +/-6.4 vs. 0.0 +/-6.0 mmHg; P = 0.003）和舒张压（6.7 +/-5.0 vs.-0.6 +/-3.6 mm Hg; P = 0.001）BP盐敏感性与无反应者（低于高盐诱导的P-MBG增加的中位数）。此外，男性受试者的高盐与低盐时MBG排泄率与年龄呈正相关，而女性受试者的相关性不明显。我们的结论是，在男性MBG增加24小时动脉血压，4周的高盐诱导MBG反应伴随着显着增加盐敏感性。然而，这些模式似乎是性别特异性的，并且在人类女性中未观察到，这与我们先前的出版物一致（安德森等人，美国生理学杂志，2008年）。 接下来，我们对5个月大的Wistar大鼠（n = 16）进行4周的盐负荷（在饮用水中的2%NaCl）。在高盐饮食的最后一周期间，对来自高盐摄入组的大鼠施用媒介物（SALT; n = 8）或抗MBG单克隆抗体（mAb; 50 μ g/kg）（SALT-AB; n = 8）。8只大鼠在研究期间保持正常盐摄入量（CTRL组）。测定血压、红细胞Na/K-ATP酶活性、血浆和24小时尿MBG水平以及主动脉移植物对硝普钠（SNP）血管舒张作用的敏感性。主动脉胶原丰度测定化学方法。 在SALT组与CTRL组的大鼠中，MBG水平升高与在不存在BP变化的情况下红细胞Na/K-ATP酶的抑制相关。高盐摄入伴随着主动脉胶原蛋白丰度增加2.5倍，以及内皮素-1诱导收缩后主动脉外植体对SNP血管舒张作用的敏感性降低。在SALT-AB组中，所有NaCl介导的作用均被MBG的免疫中和逆转。因此，在年轻的血压正常的大鼠高盐摄入可以诱导血管纤维化，通过压力非依赖性/MBG依赖性机制，这种重塑是减少MBG的免疫中和。 因此，年龄依赖性盐敏感性的BP增加与MBG的变化在男性，但不是在女性。在一项动物盐负荷研究中，在血压正常的年轻大鼠中，MBG升高与缺乏盐敏感性的主动脉纤维化和舒张减少相关，表明MBG的促纤维化作用可能与压力无关。

In the first clinical study 39 healthy subjects (53 +/- 11 years old; 20 males and 19 females) had a total daily NaCl intake of 50 mmol (low-salt) and 150 mmol (high-salt) for 4 weeks each, in random order. Arterial BP and MBG levels in plasma were measured at baseline (unstandardized salt intake) and after high- and low-salt intake. At baseline, plasma MBG (P-MBG) was related to 24-hour systolic (r= 0.43, P=0.007) and diastolic (r=0.32, P=0.047) BP. Interestingly, gender specific analyses revealed that these relationships were significant in males only. Compared to low-salt, high-salt diet increased P-MBG (P=0.029), mainly driven by results in men. Male P-MBG responders, who demonstrated the largest delta P-MBG between low-salt and high-salt intake, had markedly enhanced systolic (10.4 +/- 6.4 vs. 0.0 +/- 6.0 mmHg; P=0.003) and diastolic (6.7 +/- 5.0 vs. -0.6 +/- 3.6 mm Hg; P=0.001) BP salt-sensitivity vs. non-responders (below median of high-salt induced P-MBG increase), correspondently. In addition, ratio of MBG excretion on a high salt to the low salt positively correlated with age in male participants, but not in female. We concluded that in males MBG increases with 24-hour arterial BP, and 4-week of high-salt induced MBG response is accompanied by marked increase in salt sensitivity. However, these patterns seem to be gender specific and are not observed in females in humans, which is in accordance with our previous publication (Anderson et.al. Am J Physiol. 2008). Next, we salt loaded (2% NaCl in drinking water) 5-month old Wistar rats for 4 weeks (n=16). Rats from the group on a high salt intake were administered vehicle (SALT; n=8) or anti-MBG monoclonal antibody (mAb; 50 ug/kg) (SALT-AB; n=8) during the last week of high salt diet. Eight rats were kept on a normal salt intake for the duration of the study (CTRL group). BP, activity of erythrocyte Na/K-ATPase, levels of MBG in plasma and 24-hr urine, and sensitivity of aortic explants to the vasorelaxant effect of sodium nitropusside (SNP) were measured. Aortic collagen abundance was determined immunohistochemically. In rats from SALT vs. CTRL groups, heightened levels of MBG were associated with inhibition of erythrocyte Na/K-ATPase in the absence of BP changes. High salt intake was accompanied by a 2.5-fold increase in aortic collagen abundance and by a reduction of sensitivity of aortic explants to the vasorelaxant effect of SNP following endothelin-1-induced constriction. In the SALT-AB group, all NaCl-mediated effects were reversed by immunoneutralization of MBG. Thus, high salt intake in young normotensive rats can induce vascular fibrosis via pressure-independent/MBG-dependent mechanisms, and this remodeling is reduced by immunoneutralization of MBG. Thus, age-dependent salt-sensitivity of BP increases in parallel with MBG changes in men, but not in women. In an animal salt-loading study, MBG elevation was associated with fibrosis and reduced relaxation of aorta in the absence of salt-sensitivity in young normotensive rats, indicating that pro-fibrotic effect of MBG may be pressure-independent.