Ferrari Patrizia, Ferrandi Mara, Valentini Giovanni, Manunta Paolo, Bianchi Giuseppe
Prassis Istituto di Ricerche Sigma-Tau, Settimo Milanese, Milano, Italy.
Med Hypotheses. 2007;68(6):1307-14. doi: 10.1016/j.mehy.2006.07.058. Epub 2006 Nov 9.
Essential hypertension is a heterogeneous multifactorial syndrome associated with a high cardiovascular risk. A multiple choice of antihypertensive drugs is available; however, a high individual variability to the antihypertensive therapy is still responsible for a modest reduction of the CV risk and not satisfactory control of blood pressure levels. The success of future hypertension treatment will depend upon the understanding of the genetic molecular mechanisms operating in subsets of patients, and the ability of new drugs to specifically correct such alterations. 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 cardiovascular alterations have also been associated with adducin and EO. Rostafuroxin is a new oral antihypertensive agent able to selectively antagonize adducin and EO hypertensive 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 normalizes the enhanced activity of the Na-K pump induced by adducin mutation and antagonizes the EO triggering of the Src-EGFr-dependent signaling pathway leading to renal Na-K pump, and ERK Tyrosin phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by 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. Currently, a phase II multicenter European clinical trial is ongoing for providing the proof of concept that such a compound is effective in the subset of patients where these two mechanisms are at work.
原发性高血压是一种异质性多因素综合征，与心血管高风险相关。有多种抗高血压药物可供选择；然而，抗高血压治疗的个体差异较大，这仍然导致心血管风险仅适度降低，且血压水平控制不理想。未来高血压治疗的成功将取决于对患者亚组中运行的遗传分子机制的理解，以及新药特异性纠正此类改变的能力。在原发性高血压中观察到的肾小管钠（Na⁺）重吸收异常的决定机制中，有两种机制尤为重要：细胞骨架蛋白α - 内收蛋白的多态性和内源性哇巴因（EO）循环水平升高。两者均导致肾钠钾泵的活性和表达增加，而肾钠钾泵是肾小管钠转运的驱动力。心血管的形态和功能改变也与内收蛋白和EO有关。罗斯他福辛是一种新型口服抗高血压药物，能够选择性拮抗内收蛋白和EO的高血压及分子效应。在代表内收蛋白和EO机制的动物模型中，它在降低血压和预防器官肥大方面具有高效能和有效性。在分子水平上，在肾脏中，罗斯他福辛使由内收蛋白突变引起的钠钾泵增强活性恢复正常，并拮抗EO触发的Src - EGFr依赖性信号通路，该通路导致肾钠钾泵以及ERK酪氨酸磷酸化和激活。在血管系统中，它使由哇巴因引起的肌源性张力增加恢复正常。非常高的安全系数以及与其他血压调节机制无相互作用，再加上高血压患者中高耐受性和有效性的初步证据，表明罗斯他福辛是旨在拮抗内收蛋白和EO高血压机制的新型抗高血压药物的首个实例。目前，一项欧洲多中心II期临床试验正在进行，以提供该化合物在这两种机制起作用的患者亚组中有效的概念验证。
