Ferrandi M, Molinari I, Bianchi G, Ferrari P
Prassis sigma tau Research Institute, Milan, Italy.
Cell Mol Biol (Noisy-le-grand). 2006 Dec 30;52(8):15-8.
Experimental and clinical evidence indicates that Endogenous Ouabain (EO) and Adducin polymorphism play a pathogenetic role in hypertension and related organ complications. These effects occur through a complex interaction of genetic molecular mechanisms regulating renal sodium reabsorption and vascular function. The activation of a Na-K ATPase-Src-EGFr-ERK signaling pathway within the restricted membrane subdomains of caveolae by Ouabain has been associated to hypertension and cardiac remodeling. Rostafuroxin (PST 2238) is a novel anti-hypertensive compound able to selectively antagonize EO/Ouabain and Adducin hypertensive effect and Ouabain-induced cardiac hypertrophy in rats. Studies have been conducted in vivo and in a cell-free system to prove that Rostafuroxin exerts its antihypertensive and antihypertrophic effects by antagonizing the Src-dependent signaling triggered by Ouabain. At the vascular level, Rostafuroxin antagonizes the Ouabain-mediated increase of myogenic vascular tone. This peculiar and novel mechanism of action, together with a good tolerability and efficacy both in animal models and hypertensive patients, make Rostafuroxin the prototype of a new class of antihypertensive compounds able to antagonize EO/ Ouabain and Adducin molecular effects.
实验和临床证据表明，内源性哇巴因（EO）和内收蛋白多态性在高血压及相关器官并发症的发病机制中起作用。这些作用是通过调节肾钠重吸收和血管功能的遗传分子机制的复杂相互作用而发生的。哇巴因在小窝的受限膜亚域内激活钠钾ATP酶-Src-表皮生长因子受体-细胞外信号调节激酶信号通路，这与高血压和心脏重塑有关。罗斯他福辛（PST 2238）是一种新型抗高血压化合物，能够选择性拮抗EO/哇巴因和内收蛋白的高血压作用以及哇巴因诱导的大鼠心脏肥大。已经在体内和无细胞系统中进行了研究，以证明罗斯他福辛通过拮抗哇巴因触发的Src依赖性信号传导发挥其抗高血压和抗肥厚作用。在血管水平上，罗斯他福辛拮抗哇巴因介导的肌源性血管张力增加。这种独特的新作用机制，以及在动物模型和高血压患者中良好的耐受性和疗效，使罗斯他福辛成为能够拮抗EO/哇巴因和内收蛋白分子效应的新型抗高血压化合物的原型。
