PST 2238: A New Antihypertensive Compound that Modulates Na<sup>+</sup>,K<sup>+</sup>‐ATPase and Antagonizes the Pressor Effect of OLF

Ferrari, Paolo; Ferrandi, Mara; Torielli, Lucia; Tripodi, Grazia; Melloni, P.; Bianchi, Giuseppe

doi:10.1111/j.1527-3466.1999.tb00003.x

Cited by 54 publications

(123 citation statements)

References 59 publications

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“…Ouabain infusion in rats increased SBP, and rostafuroxin treatment at 100 mg/kg per day for 8 weeks antagonized this ouabaininduced effect (Fig. 3A), confirming previous data (Ferrari et al, 1998). Neither ouabain nor rostafuroxin affected HR (control, 350 6 6.3, n 5 15; OHR, 355 6 7.5, n 5 15; OHR 1 rostafuroxin, 358 6 9 beats/min, n 5 15).…”

Section: Rat Modelssupporting

confidence: 78%

“…The pharmacologic characteristics of the compound are described elsewhere (Quadri et al, 1997;Ferrari et al, 1998Ferrari et al, , 1999a.…”

Section: Chemicalsmentioning

confidence: 99%

“…For the second model, OHR rats, hypertension was induced in male Sprague-Dawley rats, 5 weeks old and weighing 110-120 g, by subcutaneous infusion of ouabain (15 mg/kg per day, n 5 30; SigmaAldrich, St. Louis, MO) with osmotic minipumps (Alzet; Charles River, Calco, Italy) for 12 weeks, as previously described (Ferrari et al, 1998). Normotensive control rats (n 5 15) received sterile saline solution through osmotic minipumps.…”

Section: Animal Modelsmentioning

confidence: 99%

“…OHR rats were obtained by a chronic ouabain infusion with osmotic minipumps releasing 15 mg/kg per day for 12 weeks, as previously described (Ferrari et al, 1998).…”

Section: Rat Modelsmentioning

confidence: 99%

“…These studies have shown that mutant a-adducin and ouabain activate Src tyrosine kinase and the Src-dependent Na,K-ATPase phosphorylation and its signaling network, associated with an overall increase of renal tubular sodium reabsorption and blood pressure (BP) (Ferrandi et al, 2010a). Rostafuroxin, a novel antihypertensive compound (Quadri et al, 1997), disrupts mutant a-adducin-and ouabainmediated interactions, favoring the normalization of renal Src-Na, K-ATPase signaling and BP in hypertensive rats (Ferrari et al, 1998(Ferrari et al, , 1999aFerrandi et al, 2010a) and in patients carrying a specific genetic profile that includes genes encoding for adducin variants and enzymes controlling ouabain synthesis and transport (Lanzani et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant b-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducinand ouabain-activated Na,K-ATPase, may protect podocytes from adducin-and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant b-adducin and ouabain hypertensive rats were orally treated with 100 mg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant a-adducin or b-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10 29 M ouabain were cultured with 10 29 M rostafuroxin. The results indicated that mutant b-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant b-adducin-and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant b-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.

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Section: Rat Modelssupporting

confidence: 78%

“…The pharmacologic characteristics of the compound are described elsewhere (Quadri et al, 1997;Ferrari et al, 1998Ferrari et al, , 1999a.…”

Section: Chemicalsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

“…OHR rats were obtained by a chronic ouabain infusion with osmotic minipumps releasing 15 mg/kg per day for 12 weeks, as previously described (Ferrari et al, 1998).…”

Section: Rat Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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Rostafuroxin: An ouabain-inhibitor counteracting specific forms of hypertension

Ferrari

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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.

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Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

Blaustein

Hamlyn

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Salt retention as a result of chronic, excessive dietary salt intake, is widely accepted as one of the most common causes of hypertension. In a small minority of cases, enhanced Na+ reabsorption by the kidney can be traced to specific genetic defects of salt transport, or pathological conditions of the kidney, adrenal cortex, or pituitary. Far more frequently, however, the salt retention may be the result of minor renal injury or small genetic variation in renal salt transport mechanisms. How the salt retention actually leads to the increase in peripheral vascular resistance (the hallmark of hypertension) and the elevation of blood pressure remain an enigma. Here we review the evidence that endogenous ouabain (an adrenocortical hormone), arterial smooth muscle α2 Na+ pumps, type-1 Na/Ca exchangers, and receptor- and store-operated Ca2+ channels play key roles in the pathway that links salt to hypertension. We discuss cardenolide structure-function relationships in an effort to understand why prolonged administration of ouabain, but not digoxin, induces hypertension, and why digoxin is actually anti-hypertensive. Finally, we summarize recent observations which indicate that ouabain upregulates arterial myocyte Ca2+ signaling mechanisms that promote vasoconstriction, while simultaneously downregulating endothelial vasodilator mechanisms. In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension.

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PST 2238: A New Antihypertensive Compound that Modulates Na⁺,K⁺‐ATPase and Antagonizes the Pressor Effect of OLF

Cited by 54 publications

References 59 publications

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Rostafuroxin: An ouabain-inhibitor counteracting specific forms of hypertension

Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

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PST 2238: A New Antihypertensive Compound that Modulates Na+,K+‐ATPase and Antagonizes the Pressor Effect of OLF

Cited by 54 publications

References 59 publications

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Rostafuroxin: An ouabain-inhibitor counteracting specific forms of hypertension

Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

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PST 2238: A New Antihypertensive Compound that Modulates Na⁺,K⁺‐ATPase and Antagonizes the Pressor Effect of OLF