LAUSR

Objective: We have shown that rostafuroxin (ROSTA), an antagonist of endogenous ouabain (OUA), block the biding of OUA to Na+ K+ -ATPase and inhibits the cSRC downstream activation in mesenteric resistance arteries (MRA), which ameliorates endothelial dysfunction and oxidative stress, as reduces hypertension in deoxycorticosterone acetate (DOCA)-salt rats. In addition, MRA of DOCA-salt rats also present the hypertrophic inward remodeling with stiffness. Moreover, the chronic treatment with OUA induces hypotrophic inward remodeling with stiffness in MRA. In line with these results we investigate the role of endogenous OUA on remodeling and stiffness in MRA of DOCA-salt rats. Design and method: A hypertensive model was established in uninephrectomized Wistar rats using DOCA-salt. After 5 weeks DOCA-salt treatment, with high systolic blood pressure (SBP) stabilization, this hypertensive model was divided into two groups: DOCA-salt and DOCA-salt co-treated with ROSTA (1 mg/kg per day gavage, 3 weeks). The SBP was measured using the tail-cuff method, and vascular remodeling was assessed in MRA using a pressure myograph. Histological and western blot analysis were performed in MRA. Results: Our results reinforce that ROSTA treatment reduces SBP in DOCA-salt rats, but did not restore it to control levels. For the first time, the results suggest that ROSTA ameliorates the remodeling and stiffness observed in MRA of DOCA-salt rats, enhancing the luminal diameter and distensibility, reducing the cross-section area and wall/lumen ratio as well as shifting to the right the stress-strain curve in MRA. ROSTA restores collagen type I/III ratio, internal elastic lamina thickness, tyrosine kinase Src phosphorylation (Tyr418), as well EGFR, cRaf, ERK, p38MAPK, TGF&bgr;1, CTGF, and collagen I protein expression in MRA from DOCA-salt rats. Conclusions: The results suggested that ROSTA reduces hypertension, the hypertrophic inward remodeling and the augmented wall/lumen ratio in MRA of DOCA-salt rats. In addition, endogenous OUA emerges as an important mechanism to induce vascular stiffness via Na+ K+ -ATPase/ cSRC/ EGFR/ cRas/ ERK/ p38MAPK/ CTGF/ TGF&bgr;1 pathway in MRA. These results reinforce the idea that endogenous OUA is a putative target for the treatment of vascular adjustments present in hypertension.