Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive α1 Na+-K+-ATPase
Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive α1 Na+-K+-ATPase
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DOI：
10.1152/ajpheart.00285.2009
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发表时间：
2009-06-01
影响因子：
4.8
通讯作者：
Lorenz, John N.
中科院分区：
文献类型：
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作者：
Wansapura, Arshani N.;Lasko, Valerie;Lorenz, John N.
Wansapura AN，Lasko V，Xie Z，Fedorova OV，Bagrov AY，Lingrel JB，Lorenz JN. Marinobufagenin增强哇巴因敏感性α（1）Na+-K+-ATP酶小鼠的心肌收缩力Am J Physiol Heart Circ Physiol 296：H1833-H1839，2009.首次发表于2009年4月17日; doi：10.1152/ajpheart.00285.2009。内源性Na+泵抑制剂被认为发挥重要的（病理）生理作用，并在哺乳动物循环中以两种不同的化学形式存在：强心内酯，如哇巴因，和蟾蜍二烯内酯，如海蟾毒配基（MBG）。尽管在大多数物种中所有α Na+-K+-ATP酶亚型（α（1-4））对哇巴因敏感，但在大鼠和小鼠中，普遍表达的α（1）Na+-K+-ATP酶对哇巴因具有抗性。我们先前已经证明，选择性修饰小鼠体内α（1）或α（2）Na+-K+-ATP酶亚基的假定哇巴因结合位点，可显著改变外源性应用强心内酯的强心作用。为了确定哇巴因结合位点是否也与MBG相互作用，以及这种相互作用是否发挥功能性作用，我们评估了α 1抵抗/α 2抵抗患者的心血管功能。（α（R/R）（1）α（R/R）（2）），α（1）敏感/α（2）耐药（α（S/S）（1）α（R/R）（2））和α（1）-抗性/α（2）-敏感小鼠（α（R/R）（1）α（S/S）（2），野生型）。在基线和MBG分级输注期间，通过心导管检查评估体内心血管指标。靶向小鼠的基线测量值无差异，表明血流动力学和心脏功能正常。与α（R/R）（1）α（R/R）（2）和野生型小鼠相比，0.025、0.05和0.1 nmol.min（-1）.g体重的MBG在更大程度上显著增加了α（S/S）（1）α（R/R）（2）小鼠的心脏性能。与α（R/R）（1）α（R/R）（2）和α（R/R）（1）α（S/S）（2）小鼠相比，在较高浓度的MBG下，α（S/S）（1）α（R/R）（2）小鼠的LVdP/dt（max）增加更大（P < 0.05）。这些结果表明，MBG与α（1）Na+-K+-ATP酶亚基的哇巴因结合位点相互作用，从而影响心肌收缩力。
Wansapura AN, Lasko V, Xie Z, Fedorova OV, Bagrov AY, Lingrel JB, Lorenz JN. Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive alpha(1) Na+-K+-ATPase. Am J Physiol Heart Circ Physiol 296: H1833-H1839, 2009. First published April 17, 2009; doi:10.1152/ajpheart.00285.2009.-Endogenous Na+ pump inhibitors are thought to play important (patho) physiological roles and occur in two different chemical forms in the mammalian circulation: cardenolides, such as ouabain, and bufadienolides, such as marinobufagenin (MBG). Although all alpha Na+-K+-ATPase isoforms (alpha(1-4))are sensitive to ouabain in most species, in rats and mice the ubiquitously expressed alpha(1) Na+-K+-ATPase is resistant to ouabain. We have previously shown that selective modification of the putative ouabain binding site of either the alpha(1) or alpha(2) Na+-K+-ATPase subunit in mice substantially alters the cardiotonic influence of exogenously applied cardenolides. To determine whether the ouabain binding site also interacts with MBG and if this interaction plays a functional role, we evaluated cardiovascular function in alpha(1)-resistant/alpha(2)-resistant (alpha(R/R)(1)alpha(R/R)(2)), alpha(1)-sensitive/alpha(2)-resistant (alpha(S/S)(1)alpha(R/R)(2)), and alpha(1)-resistant/alpha(2)-sensitive mice (alpha(R/R)(1)alpha(S/S)(2), wild type). Cardiovascular indexes were evaluated in vivo by cardiac catheterization at baseline and during graded infusions of MBG. There were no differences in baseline measurements of targeted mice, indicating normal hemodynamics and cardiac function. MBG at 0.025, 0.05, and 0.1 nmol.min(-1).g body wt(-1) significantly increased cardiac performance to a greater extent in alpha(S/S)(1)alpha(R/R)(2) compared with alpha(R/R)(1)alpha(R/R)(2) and wild-type mice. The increase in LVdP/dt(max) in alpha(S/S)(1)alpha(R/R)(2) mice was greater at higher concentrations of MBG compared with both alpha(R/R)(1)alpha(R/R)(2) and alpha(R/R)(1)alpha(S/S)(2) mice (P < 0.05). These results suggest that MBG interacts with the ouabain binding site of the alpha(1) Na+-K+-ATPase subunit and can thereby influence cardiac inotropy.