A new antihypertensive agent that antagonizes the prohypertensive effect of endogenous Ouabain and Adducin

Paolo Manunta, Mara Ferrandi, Elisabetta Messaggio, Patrizia Ferrari

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Endgenous Ouabain (EO) and Adducin enhance the Na-K pump function and play an important role in sodium homeostasis and blood pressure (BP) regulation. In the general population, plasma EO modulates BP either by inhibiting the prohypertensive effect of an excessive salt intake or counteracting the depressor action of normal-moderate salt intake. Almost 50% of hypertensive patients have increased circulating plasma levels of EO. EO has been associated both to left ventricular dysfunction and hypertrophy. A new antihypertensive agent, PST2238, (17β-(3-furyl)-50β-androstan-3β, 14β, 17α-triol a digitoxigenin derivative) able to selectively antagonize both the EO and adducin prohypertensive and molecular effects, has been developed. In hypertensive rats (MHS strain) carrying both adducin mutations and increased plasma EO and in ouabain-infused rats (OS), PST2238 lowers BP by normalizing the renal Na-K pump function. In OS rats, PST antagonized the cardiac and renal pro-hypertrophic ouabain effect associated to the activation of the Src-EGFr-ERK1/2 signaling cascade. Phase 1 clinical studies demonstrated a high tolerability of PST2238. In a preliminary phase 2 study on 42 mild never-treated hypertensive patients, PST2238 given for 3 months at 0.5 mg/day, significantly reduced BP in subjects with moderate salt intake, implying that it may be selectively effective in conditions where EO plays a prohypertensive role. In conclusion, PST2238, because of its peculiar action mechanism, represents a new tool to disentangle the complex relationship between salt intake, genetic control of renal sodium handling and EO effect.

Original languageEnglish
Pages (from-to)61-66
Number of pages6
JournalCardiovascular and Hematological Agents in Medicinal Chemistry
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 2006

Fingerprint

Ouabain
Antihypertensive Agents
Salts
Blood Pressure
Kidney
Digitoxigenin
Sodium
adducin
Left Ventricular Dysfunction
Left Ventricular Hypertrophy
Homeostasis
Mutation

Keywords

  • Genetic
  • Hypertension
  • Hypertrophy
  • Na-K ATPase
  • Rat

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Hematology
  • Pharmacology

Cite this

A new antihypertensive agent that antagonizes the prohypertensive effect of endogenous Ouabain and Adducin. / Manunta, Paolo; Ferrandi, Mara; Messaggio, Elisabetta; Ferrari, Patrizia.

In: Cardiovascular and Hematological Agents in Medicinal Chemistry, Vol. 4, No. 1, 01.2006, p. 61-66.

Research output: Contribution to journalArticle

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