Plasma nitrate, dietary nitrate, blood pressure, and vascular health biomarkers: a GRADE-Assessed systematic review and dose-response meta-analysis of randomized controlled trials

Abstract Background Hypertension and vascular dysfunction are major health concerns, and studies have suggested different interventions, including dietary nitrate (NO3), to improve it. We sought to elucidate the effects of dietary NO3 on plasma NO3 and nitrite (NO2) levels and to determine the shape of the effect of dietary NO3 on blood pressure (BP) and vascular health biomarkers. Methods PubMed, Scopus, and Web of Science were searched up to February 2024 for eligible randomized controlled trials (RCTs). The pooled results were reported as weighted mean differences (WMD) and 95% confidence intervals (CIs). Results Our analysis of 75 RCTs involving 1823 participants revealed that per each millimole (mmol) increase in the administered NO3 dose, both acute (WMD: 32.7µmol/L; 95%CI: 26.1, 39.4) and chronic-term (WMD: 19.6µmol/L; 95%CI: 9.95, 29.3) plasma NO3 levels increased. Per each mmol increase in NO3 intake, a reduction in systolic BP levels was observed in the acute (WMD: -0.28mmHg; 95%CI: -0.40, -0.17), short-term (WMD: -0.24mmHg; 95%CI: -0.40, -0.07), and medium-term (WMD: -0.48mmHg; 95%CI: -0.71, -0.25) periods. Furthermore, a decrease in diastolic BP for each mmol increase in NO3 intake (WMD: -0.12 mmHg; 95% CI: -0.21, -0.03) was shown. Moreover, a linear dose-response relationship was indicated between each mmol of NO3 intake and medium-term pulse wave velocity (WMD: -0.07 m/s; 95%CI: -0.11, -0.03), medium-term flow-mediated dilation (WMD: 0.30%; 95%CI: 0.15, 0.46), and medium-term augmentation index (WMD: -0.57%; 95%CI: -0.98, -0.15). Conclusion We observed dose-dependent increases in plasma NO3 and NO2 levels, along with consequent reductions in BP and enhancements in vascular health following dietary NO3 supplementation. Future high-quality, population-specific studies with optimized dietary NO3 dosages are needed to strengthen the certainty of the evidence. Registration The protocol for this systematic review was registered in PROSPERO under the registration number CRD42024535335.