Marinobufagenin, an endogenous alpha-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats.
Marinobufagenin, an endogenous alpha-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats.
复制标题
DOI：
--
复制
发表时间：
2001
期刊：
影响因子：
8.3
通讯作者：
O. Fedorova;N. I. Kolodkin;N. Agalakova;E. Lakatta;A. Bagrov
中科院分区：
文献类型：
--
作者：
O. Fedorova;N. I. Kolodkin;N. Agalakova;E. Lakatta;A. Bagrov
Dahl 盐敏感大鼠 (DS) 的 Na(+)/K(+)-ATP 酶 α-1 亚基发生突变，表现出压力尿钠排泄受损，在高盐饮食下，保留 Na(+) 并表现出血压升高。最近，我们发现哺乳动物组织含有蟾蜍二烯内酯Na(+)/K(+)-ATP酶抑制因子marinobufagenin (MBG)，它对α-1的亲和力比对α-3钠泵亚型的亲和力更大。本研究调查了MBG 在高氯化钠摄入情况下的DS 高血压中的可能作用。 8 只 DS 和 8 只 Dahl 耐盐大鼠 (DR) 接受 8% NaCl 饮食。两周内，DS 中的收缩压升高（第 2 周为 162+/-9 mm Hg，基线为 110+/-2 mm Hg，P<0.01），而 DR 中收缩压升高较少（第 2 周为 124+/-3 mm Hg，基线为 112+/-2 mm Hg）。 DS 中 MBG 的肾排泄增加了 4 倍（38.9+/-7.6 pmol 对比基线 9.1+/-1.3 pmol，P<0.01），但 DR 中仅增加 25%（13.2+/-0.9 pmol 对比基线 10.3+/-0.7 pmol）。两种菌株中内源哇巴因的排泄没有变化。通过两步反相高效液相色谱 (HPLC) 从高血压 DS 的尿液中纯化 MBG 免疫反应物质，并与植物哇巴因和两栖动物 MBG 比较其抑制大鼠肾脏 Na(+)/K(+)-ATPase（仅表达 α-1 Na(+)/K(+)-ATPase 亚型）的能力。与哇巴因 (IC(50)=248 µmol/L) 不同，连续稀释、HPLC 纯化的 DS 和真实 MBG 的 MBG 免疫反应性可有效抑制大鼠肾 Na(+)/K(+)-ATP 酶（IC(50) 分别为 70 和 78 nmol/L）。我们的结果表明，α-1 Na(+)/K(+)-ATPase 配体 MBG 可以促进高血压 DS 中的尿钠排泄。 MBG 作为哇巴因抗性 α-1 Na(+)/K(+)-ATP 酶亚基（即肾脏的主要钠泵亚型）的选择性抑制剂，正如假定的利尿钠激素所预期的那样。
Dahl salt-sensitive rats (DS), which have a mutation in the alpha-1 subunit of Na(+)/K(+)-ATPase, exhibit impaired pressure natriuresis and on a high-salt diet, retain Na(+) and exhibit increased blood pressure. Recently, we have shown that mammalian tissues contain a bufadienolide Na(+)/K(+)-ATPase inhibitory factor, marinobufagenin (MBG), that exhibits greater affinity for the alpha-1 than alpha-3 sodium pump isoform. The present study investigated the possible role of MBG in hypertension in DS on a high NaCl intake. Eight DS and 8 Dahl salt-resistant rats (DR) were placed on an 8% NaCl diet. Within 2 weeks, systolic blood pressure increased in DS (162+/-9 mm Hg at week 2 versus 110+/-2 mm Hg in baseline, P<0.01), and increased less in DR (124+/-3 mm Hg at week 2 versus 112+/-2 mm Hg in baseline). Renal excretion of MBG increased 4-fold (38.9+/-7.6 pmol versus 9.1+/-1.3 pmol in baseline, P<0.01) in DS, but by only 25% in DR (13.2+/-0.9 pmol versus 10.3+/-0.7 pmol in baseline). Excretion of endogenous ouabain did not change in either strain. MBG-immunoreactive material was purified from the urine of hypertensive DS by means of 2 steps of reverse-phase high performance liquid chromatography (HPLC) and compared with plant ouabain and amphibian MBG for its ability to inhibit the Na(+)/K(+)-ATPase from rat kidney (which expresses only alpha-1 Na(+)/K(+)-ATPase isoform). Unlike ouabain (IC(50)=248 micromol/L), serially diluted, HPLC-purified MBG immunoreactivity from DS and authentic MBG potently inhibited rat kidney Na(+)/K(+)-ATPase (IC(50)=70 and 78 nmol/L, respectively). Our results suggest that an alpha-1 Na(+)/K(+)-ATPase ligand, MBG, is elaborated to promote natriuresis in hypertensive DS. MBG acts as a selective inhibitor of the ouabain-resistant alpha-1 Na(+)/K(+)-ATPase subunit, ie, the major sodium pump isoform of the kidneys, as would be expected of a putative natriuretic hormone.