Rostafuroxin (PST 2238)

Description:

IC50: 2 μM for Na+-K+-ATPase

Two mechanisms are involved in determining the abnormalities of tubular Na+ reabsorption observed in hypertension: the polymorphism of the cytoskeletal protein α-adducin and the increased circulating endogenous ouabain (EO) levels. Both lead to increased activity and expression of the renal Na+-K+ pump, which is the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a novel oral antihypertensive agent able to selectively antagonize EO, adducin pressor, and molecular effects.

In vitro: At molecular level, in the kidney, Rostafuroxin antagonizes EO by 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 [1].

In vivo: Rostafuroxin reduces blood pressure without affecting heart rate, and restores the normal activity of the renal Na+-K+-ATPase in MHS rats when orally treated at doses from 1 to 100 μg/kg/day. Similarly, NUA rats have their blood pressure normalized by rostafuroxin [1].

Clinical trial: Rostafuroxin has already satisfied safety requirements in phase I studies showing complete tolerability either after single or repeated administrations up to a dose of 10 mg/day, without showing differences in side effect patterns compared with placebo. In two small exploratory studies in patients with mild uncomplicated hypertension, rostafuroxin has been demonstrated to be effective in lowering blood pressure at oral doses from 0.1 to 1 mg/day [1].

Reference:
[1] Ferrari P, Ferrandi M, Valentini G, Bianchi G.  Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+-ATPase alterations in ouabain and adducin-dependent hypertension. Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R529-35.


Ouabain-dependent signaling in caveolae as a novel therapeutic target for hypertension.[Pubmed:17535730]

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.

Rostafuroxin: an ouabain-inhibitor counteracting specific forms of hypertension.[Pubmed:20083196]

Biochim Biophys Acta. 2010 Dec;1802(12):1254-8.

An innovative approach to the therapy of essential hypertension (EH) and the related complications has been pursued by our group with the aim of defining specific genetic-molecular mechanisms underlying the disease in sub-sets of patients. This approach is anticipated to have a major effect on the clinical practice, diagnostics and development of new drugs able to selectively target such mechanisms. The final achievement is the definition of biomarkers for identifying patients who more likely should benefit for a given therapy both in terms of efficacy and reduction of the adverse reactions. Among many, two mechanisms have been defined and addressed:Both alterations lead to hypertension, organ hypertrophy, negative vascular remodeling and increased cardiovascular risk by affecting the renal Na(+) handling, through the up-regulation of the Na(+)-K(+) pump and the activation of the Src-dependent signal transduction pathway. A novel antihypertensive agent, rostafuroxin (PST2238), has been selected and developed for its ability to correct the renal Na(+)-K(+) pump abnormalities sustained by the mutant adducin and EO-dependent mechanisms. It is endowed with high potency and efficacy in reducing blood pressure (BP) 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 mutant adducin and antagonizes the EO triggering of the Src-EGFr-dependent signaling pathway leading to renal Na(+)-K(+) pump and ERK phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by ouabain. A very high safety ratio and the absence of interaction with other mechanisms involved in BP regulation, together with 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. A recently concluded Phase II clinical trial (OASIS) has provided the proof of concept that such a compound is effective in the subset of patients where these two mechanisms are at work.

Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension.[Pubmed:16467500]

Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R529-35.

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.

Rostafuroxin(PST 2238) is a antihypertensive compound; Na,K-ATPase antognist;displaced [3H]ouabain from the dogkidney Na+,K+-ATPase with IC50 of 1.5 nM.

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