Bariatric surgery blunts nitrate-mediated improvements in cardiovascular function of overweight women by interfering with gastric S-nitrosothiol formation

Abstract

Inorganic nitrate (NO₃⁻) and nitrate-rich foods have been shown to exert antioxidative effects and lower blood pressure in experimental animal models and human clinical studies. The specific handling of nitrate, including its enterosalivary recirculation, secretion into saliva, oral microbial reduction to nitrite (NO₂⁻), and the pH-dependent nitrosative capacity in the stomach have all been recognized as being important for nitrate's beneficial effects. Obesity is of major health concern worldwide and associated with increased cardiovascular risk; whether nitrate lowers blood pressure and improves endothelial function in this setting has not been investigated. We here tested the hypotheses that i) nitrate elicits cardiovascular benefits in overweight women; and ii) these beneficial effects would be diminished in women who underwent bariatric Roux-en-Y gastric bypass (RYGB) surgery. Our controlled clinical trial included 15 women with prior RYGB surgery and 15 overweight female controls. All participants received a single dose of 0.1 mmol/kg/day nitrate in the form of a beetroot extract for 14 days. Blood collection, 24-h ambulatory blood pressure measurements and endothelial function tests were performed before and after nitrate treatment. Plasma nitrite, nitrate, and S-nitrosothiol (RSNO) concentrations were determined by ozone-based reductive chemiluminescence while thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were measured using plate-reader based assays. Nitrate reduced blood pressure and improved endothelial function in controls, but not in women with prior bariatric surgery. Nitrate also increased circulating nitrate/nitrite and RSNO levels in controls, but the latter was blunted following RYGB surgery despite even larger increases in nitrite concentrations. Similarly, nitrate increased antioxidant responses in controls but not in women with prior bariatric surgery. This is the first study to show that nitrate exerts beneficial cardiovascular effects in obesity and that the morphological/functional modifications elicited by RYGB surgery abrogates nitrate's effectiveness by preventing gastric RSNO formation.