PST 2238 a new antihypertensive compound that modulates renal Na-KATPase in genetic hypertension.

Ferrari, Paolo; Ferrandi, Mara; Torielli, Lucia; Duzzi, L; Padoani, Gloria; Minotti, E.; Melloni, P.; Bianchi, Giuseppe

doi:10.1016/s0895-7061(99)80055-7

Cited by 30 publications

(75 citation statements)

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“…PST 2238 (17/3-(3-furyl)-5~-androstan-3j9, 14i3, 17a-triol) is a digitoxigenin derivative able to displace `in vitro' ouabain from the Na-K ATPase receptor with IC50 of 2 pM (26). It does not interact `in vitro' with other receptors involved in blood pressure regulation or hormonal steroid control (26) and does not cause any cardiac effect when tested both on isolated cardiac preparations and `in vivo' (28).…”

Section: Methods and Resultsmentioning

confidence: 99%

“…In MHS rats in which the adducin polymorphism (9) and increased OLF levels are present (16), PST 2238 administered orally for 6 weeks, starting from a prehypertensive age, reduces in a dose-dependent way the development of hypertension with an EC50 of 4 pg/kg os (27). In normal Sprague Dawley rats, made hypertensive by a chronic infusion of 50 sag/kg/day of ouabain (OS rats) (26), PST 2238 completely abolishes the ouabain-dependent blood pressure increase in a dose range between 0.1 and 10 icg/kg os (26). The ability of PST 2238 to antagonize the effects of adducin mutations and ouabain (or OLF) on renal Na-K ATPase activity and expression has been demonstrated both in cultured renal cells and `in vivo.…”

Section: Methods and Resultsmentioning

confidence: 99%

“…Incubation of NRK-1 cells with PST 2238 at 10-10, 10-9 M for 5 days results in a significant reduction of pump activity to the level of normal cells which are not affected by a similar treatment (27). In wild-type NRK cells (expressing the non-mutated adducin variant), 5 days of incubation with 10-9 M ouabain induces a significant increase in Na-K pump activity at Vmax (+ 35% , p < 0.01) (26). The simultaneous presence of PST 2238 (1014 to 10_9 M) in the ouabain medium normalizes the ouabain-dependent increase of the Na-K pump at Vmax, while the compound does not have any apparent effect on the Na-K pump rate at concentrations up to 10-5 M (26).…”

Section: Cell Studiesmentioning

confidence: 91%

“…Moreover, a link between increased levels of OLF and further stimulation of the renal Na-K pump expression, has been observed when studying rat models: first, the hyperactivation of the renal Na-K pump observed in young prehypertensive MHS rats also persists in adult animals (12), with the animals observed already being hypertensive and with the above relation also being present when OLF levels were increased to maximum compared with normotensive MNS (24) ; second, chronic infusions of low doses of ouabain in normal Sprague Dawley rats not only induces a sustained form of hypertension (25) but are also associated with a stimulation of the renal Na-K pump, with these effects mimicking those observed in the genetic MHS model (26). Therefore, an up-regulation of renal Na-K pump activity and expression seems to be a common molecular alteration of forms of hypertension sustained by adducin polymorphism and/or high circulating levels of endogenous ouabain.…”

Section: Humansmentioning

confidence: 99%

“…Following this approach, among more than 800 original molecules, compound PST 2238 has been selected (26)(27)(28) for its ability to selectively displace the ouabain binding from the Na-K ATPase receptor and to be antihypertensive in experimental and genetic models of hypertension in which the above-mentioned alterations are operating.…”

Section: Humansmentioning

confidence: 99%

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PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

et al. 2000

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A primary renal alteration due to a genetic polymorphism of the cytoskeletal protein adducin associated with an up-regulation of the renal Na-K pump and increased levels of ouabainlike factor (OLF) has been identified as a possible causes of hypertension in Milan rats (MHS). This adducin polymorphism has also been found to be associated with hypertension and the blood pressure changes related to renal Na handling in humans and increased OLF levels have been found in a relevant portion of hypertensive patients. Increased activity and expression of the Na-K pump has also been observed under the following in vitro'and `in vivo' conditions: rat renal cells transfected with the `hypertensive' variant of adducin, as compared with normal cells; normal rat renal cells incubated for 5 days with 10_9 M ouabain and normal rats made hypertensive by a chronic infusion of low doses of ouabain (OS rats). An up-regulation of the Na-K pump seems therefore to be a common biochemical alteration induced both by an adducin polymorphism and/or chronic exposure to low concentrations of ouabain (or OLF). A new antihypertensive compound, PST 2238, that selectively antagonizes the pressor effect and the alteration of the renal Na-K pump induced both by an adducin polymorphism and OLF, is described. The ability of PST 2238 to lower blood pressure and normalize the Na-K pump both in MHS and OS rats suggests that this compound could be useful in the treatment of those forms of essential hypertension in which renal Na-handling alterations are associated with either adducin polymorphisms and/or increased OLF levels.(Hypertens Res 2000; 23 Suppl: S15-S19) Key Words: hypertension, adducin, ouabainlike factor, therapy, pharmacogenomic IntroductionEssential hypertension is a complex disease in which many genetic and environmental factors interact to result in a final blood pressure increase and the risk to develop specific organ complications (mainly at the cardiac, renal, and brain levels) (1, 2). Although the antihypertensive efficacy of different classes of drugs is widely recognized and is similar when large populations are compared, there is much individual variability in the response to a given therapeutical regimen (3). Population surveys have demonstrated that less than 30% of patients are adequately treated. These problems arise primarily from the lack of a complete understanding of the mechanisms that underlay the development of primary hypertension and its organ complications. Therefore, the success of a future new therapy for hypertension will depend upon our understanding of the molecular-genetic mechanisms operating in a subset of patients and the ability of the new drug to correct such a mechanism. A pharmacogenomic approach (4, 5) has been adopted by Prassis sigma-tau to develop a new class of antihypertensive compounds able to lower blood pressure by correcting a specific genetic-molecular mechanism previously demonstrated to be involved both in rat and human hypertension. As a consequence, the

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Section: Methods and Resultsmentioning

confidence: 99%

Section: Methods and Resultsmentioning

confidence: 99%

Section: Cell Studiesmentioning

confidence: 91%

Section: Humansmentioning

confidence: 99%

Section: Humansmentioning

confidence: 99%

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PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

et al. 2000

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Concentration Dependent Effect of (−)‐Epicatechin on Na⁺/K⁺‐ATPase and Ca²⁺‐ATPase Inhibition Induced by Free Radicals in Hypertensive Patients: Comparison with L‐ascorbic Acid

Kumar

Kant

Maurya

et al. 2012

Phytotherapy Research

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Although the antioxidant properties of flavonoids are well documented, it is still unclear whether these effects are dependent on radical scavenging or iron chelating activities. Oxidative stress, a state of excessive reactive oxygen species (ROS) activity, is associated with vascular disease conditions such as hypertension. Both the anti- and pro-oxidant effects of tea catechins have been implicated in the alterations of cellular functions that determine their chemoprotective and therapeutic potentials in health and diseases. The present study examined the concentration dependent (10(-7) to 10(-4) m) effects of (-)-epicatechin and L-ascorbic acid on Na(+) /K(+) -ATPase and Ca(2+) -ATPase activity in hypertensive patients and normal subjects. L-ascorbic acid has been used as a positive control to compare the effect of (-)-epicatechin. A significant (p < 0.0001) decrease in the activities of Na(+) /K(+) -ATPase and Ca(2+) -ATPase was observed in hypertensive patients compared with normal subjects. We report that (-)-epicatechin shows a significant (p < 0.001) dose-dependent protective effect against oxidative stress induced by tert-butyl hydroperoxide (t-BHP), which is manisfested as a decrease in the activity of erythrocyte Na(+) /K(+) -ATPase and Ca(2+) -ATPase, in hypertensive patients as well as normal subjects. The effect of L-ascorbic acid was also significant (p < 0.001) and was comparable with that of (-)-epicatechin.

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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 renal Na-KATPase in genetic hypertension.

Cited by 30 publications

References 0 publications

PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

Concentration Dependent Effect of (−)‐Epicatechin on Na⁺/K⁺‐ATPase and Ca²⁺‐ATPase Inhibition Induced by Free Radicals in Hypertensive Patients: Comparison with L‐ascorbic Acid

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 renal Na-KATPase in genetic hypertension.

Cited by 30 publications

References 0 publications

PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

Concentration Dependent Effect of (−)‐Epicatechin on Na+/K+‐ATPase and Ca2+‐ATPase Inhibition Induced by Free Radicals in Hypertensive Patients: Comparison with L‐ascorbic Acid

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

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Product

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Concentration Dependent Effect of (−)‐Epicatechin on Na⁺/K⁺‐ATPase and Ca²⁺‐ATPase Inhibition Induced by Free Radicals in Hypertensive Patients: Comparison with L‐ascorbic Acid