title: Rostafuroxin ameliorates endothelial dysfunction and oxidative stress in resistance arteries from deoxycorticosterone acetate-salt hypertensive rats: the role of Na+K+-ATPase/ cSRC pathway.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Camilla F
authors.initials: CF
authors.lastname: Wenceslau
authors.forename: Luciana V
authors.initials: LV
authors.lastname: Rossoni
mesh_terms: D000732:Androstanols / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D064791:Desoxycorticosterone Acetate / Q000633:toxicity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D019255:NADPH Oxidases / Q000378:metabolism; D010042:Ouabain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000732:Androstanols; D000959:Antihypertensive Agents; D017673:Sodium Chloride, Dietary; D010042:Ouabain; D064791:Desoxycorticosterone Acetate; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019255:NADPH Oxidases; D019061:src-Family Kinases; D000254:Sodium-Potassium-Exchanging ATPase; C106263:rostafuroxin