Xanthine Oxidase Inhibitor, Febuxostat Ameliorates the High Salt Intake–Induced Cardiac Hypertrophy and Fibrosis in Dahl Salt-Sensitive Rats

Abstract BACKGROUND Xanthine oxidase (XO) is a source of reactive oxygen species production in the heart. However, pathophysiological role of XO has not been clarified in hypertensive heart disease. Thus, the present study examined the impacts of high salt (HS) intake and febuxostat (Fx), a XO inhibitor in Dahl salt-sensitive (Dahl-S) rats. METHODS Eight-week old, male Dahl-S rats were fed a normal salt diet (0.6% NaCl) or a HS diet (8% NaCl) for 8 weeks. A part of the rats fed the HS diet were simultaneously treated with Fx (3 mg/kg/day). RESULTS HS intake increased blood pressure and heart weight with cardiomyocyte hypertrophy and interstitial fibrosis in the left ventricle (LV), and Fx diminished them. HS increased the XO activity 4.7-fold and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity 1.5-fold, and Fx not only blocked the XO activity but also inhibited the HS-increased NADPH oxidase activity. HS increased the expression of XO, collagen, transforming growth factor-β1 (TGF-β1), angiotensin-converting enzyme, and angiotensin II type 1 receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the LV, and Fx reduced the expression and phosphorylation of these proteins except XO. CONCLUSIONS Fx ameliorates the HS intake-induced hypertension, LV hypertrophy, and fibrosis with decreasing the TGF-β1 expression and ERK phosphorylation in Dahl-S rats. Fx also down-regulates cardiac NADPH oxidase and renin–angiotensin system. The XO inhibition may be an effective therapy for hypertensive heart disease.