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首页> 外文期刊>American Journal of Physiology >Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension.
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Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension.

机译：Rostafuroxin：一种哇巴因拮抗剂，可纠正哇巴因和依赖阿多辛的高血压患者的肾脏和血管Na + -K +-ATPase改变。

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摘要

The genetic and environmental heterogeneity of essential hypertension is responsible for the individual variability of antihypertensive therapy. An understanding of the molecular mechanisms underlying hypertension and related organ complications is a key aspect for developing new, effective, and safe antihypertensive agents able to cure the cause of the disease. Two mechanisms, among others, are involved in determining the abnormalities of tubular Na+ reabsorption observed in essential hypertension: the polymorphism of the cytoskeletal protein alpha-adducin and the increased circulating levels of endogenous ouabain (EO). Both lead to increased activity and expression of the renal Na+-K+ pump, the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a new oral antihypertensive agent able to selectively antagonize EO, adducin pressor, and molecular effects. It is endowed with high potency and efficacy in reducing blood pressure and preventing organ hypertrophy in animal models representative of both adducin and EO mechanisms. At molecular level, in the kidney, Rostafuroxin antagonizes EO triggering of the Src-epidermal growth factor receptor (EGFr)-dependent signaling pathway leading to renal Na+-K+ pump, and ERK tyrosine phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by nanomolar ouabain. A very high safety ratio and an absence of interaction with other mechanisms involved in blood pressure regulation, together with initial evidence of high tolerability and efficacy in hypertensive patients, indicate Rostafuroxin as the first example of a new class of antihypertensive agents designed to antagonize adducin and EO-hypertensive mechanisms.
机译：原发性高血压的遗传和环境异质性导致了降压治疗的个体差异。了解潜在的高血压和相关器官并发症的分子机制是开发能够治愈疾病原因的新型，有效和安全的降压药的关键方面。确定原发性高血压中观察到的肾小管Na +重吸收异常涉及两种机制：细胞骨架蛋白α-adducin的多态性和内源性哇巴因（EO）循环水平的提高。两者均导致肾Na + -K +泵的活性和表达增加，这是肾小管Na转运的驱动力。形态和功能性血管改变也与EO有关。罗他福辛（PST 2238）是一种新型的口服降压药，能够选择性拮抗EO，阿杜生加压素和分子作用。在代表adducin和EO机制的动物模型中，它具有降低血压和预防器官肥大的高效能和功效。在分子水平上，在肾脏中，罗他福辛拮抗EO触发Src-表皮生长因子受体（EGFr）依赖性信号传导途径，导致肾Na + -K +泵以及ERK酪氨酸磷酸化和激活。在脉管系统中，它可以使纳摩尔的哇巴因引起的肌张力增高正常化。极高的安全比和与血压调节相关的其他机制之间没有相互作用，以及高血压患者高耐受性和有效性的初步证据表明，罗他福辛是旨在拮抗阿杜克辛和阿霉素的新型抗高血压药的首例。 EO-高血压机制。

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