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Rostafuroxin ameliorates endothelial dysfunction and oxidative stress in resistance arteries from deoxycorticosterone acetate-salt hypertensive rats: the role of Na+K+-ATPase/ cSRC pathway.

AbstractAIMS:
Endogenous ouabain is elevated in patients and experimental models of hypertension and is associated with elevated mortality. In this context, it is reasonable to assume that a new antihypertensive drug that inhibits the deleterious effects of endogenous ouabain may be a specific pharmacological tool for hypertension treatment. Here, we investigated the effects of rostafuroxin (ROSTA), an ouabain inhibitor, on SBP, endothelial dysfunction and oxidative stress in deoxycorticosterone acetate (DOCA)-salt rats.
METHODS AND RESULTS:
A hypertensive model was established in uninephrectomized Wistar rats using DOCA-salt. After SBP stabilization, DOCA-salt rats were divided into two groups: DOCA-salt (control) and DOCA-salt treatment with ROSTA (1 mg/kg per day gavage, 3 weeks). The SBP was measured using the tail-cuff method, and vascular function was assessed in mesenteric-resistance arteries (MRAs) using a wire myograph. Nitric oxide and reactive oxygen species production were investigated. Western blot was performed to quantify protein expression. Our results indicated that ROSTA treatment decreased SBP, improved acetylcholine-induced relaxation via enhanced nitric oxide synthesis and bioavailability, decreased superoxide anion generation from NAD(P)H oxidase and cyclooxygenase-2 and reduced cytoplasmic tyrosine kinase Src phosphorylation without changes in NaKATPase activity in MRA from DOCA-salt rats.
CONCLUSION:
This study reports the critical role of endogenous ouabain in volume-dependent hypertension. In MRA from DOCA-salt rats, the binding of endogenous ouabain to NaK-ATPase results in downstream c-SRC activation, oxidative stress and endothelial dysfunction. Endogenous ouabain is a putative target for the treatment of hypertension, and ROSTA may represent a novel therapeutic approach.
AuthorsCamilla F Wenceslau, Luciana V Rossoni
JournalJournal of hypertension (J Hypertens) Vol. 32 Issue 3 Pg. 542-54 (Mar 2014) ISSN: 1473-5598 [Electronic] England
PMID24309491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Androstanols
  • Antihypertensive Agents
  • Sodium Chloride, Dietary
  • Ouabain
  • Desoxycorticosterone Acetate
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • NADPH Oxidases
  • src-Family Kinases
  • Sodium-Potassium-Exchanging ATPase
  • rostafuroxin
Topics
  • Androstanols (pharmacology)
  • Animals
  • Antihypertensive Agents (pharmacology)
  • Blood Pressure (drug effects, physiology)
  • Cyclooxygenase 2 (metabolism)
  • Desoxycorticosterone Acetate (toxicity)
  • Endothelium, Vascular (drug effects, physiopathology)
  • Humans
  • Hypertension (drug therapy, etiology, physiopathology)
  • Male
  • Mesenteric Arteries (drug effects, physiopathology)
  • NADPH Oxidases (metabolism)
  • Ouabain (antagonists & inhibitors, metabolism)
  • Oxidative Stress (drug effects)
  • Rats
  • Rats, Wistar
  • Signal Transduction (drug effects)
  • Sodium Chloride, Dietary (toxicity)
  • Sodium-Potassium-Exchanging ATPase (metabolism)
  • Vascular Resistance (drug effects)
  • Vasodilation (drug effects)
  • src-Family Kinases (metabolism)

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