Renal handling of nitrate in women and men with elevated blood pressure

Abstract

Aim: The inorganic anions nitrate and nitrite are oxidation products of nitric oxide (NO) that have often been used as an index of NO generation. More than just being surrogate markers of NO, nitrate/nitrite can recycle to bioactive NO again. Nitrate is predominantly eliminated via the kidneys; however, there is less knowledge regarding tubular handling. The aim of this study, as part of a large randomized controlled trial, was to explore potential sex differences in renal nitrate handling during low and high dietary nitrate intake. We hypothesized that renal clearance and excretion of nitrate are higher in men compared to women. Methods: In prehypertensive and hypertensive individuals (n = 231), nitrate and nitrite were measured in plasma and urine at low dietary nitrate intake (baseline) and after 5 weeks supplementation with nitrate (300 mg potassium nitrate/day) or placebo (300 mg potassium chloride/day). Twenty-four hours ambulatory blood pressure recordings and urine collections were conducted. Results: At baseline, plasma nitrate and nitrite, as well as the downstream marker of NO signalling cyclic guanosine monophosphate, were similar in women and men. Approximately 80% of filtered nitrate was spared by the kidneys. Urinary nitrate concentration, amount of nitrate excreted, renal nitrate clearance (Cnitrate) and fractional excretion of nitrate (FEnitrate) were lower in women compared to men. No association was observed between plasma nitrate concentrations and glomerular filtration rate (GFR), nor between FEnitrate and GFR in either sex. After 5 weeks of nitrate supplementation plasma nitrate and nitrite increased significantly, but blood pressure remained unchanged. FEnitrate increased significantly and the sex difference observed at baseline disappeared. Conclusion: Our findings demonstrate substantial nitrate sparing capacity of the kidneys, which is higher in women compared to men. This suggests higher tubular nitrate reabsorption in women but the underlying mechanism(s) warrants further investigation.