Craig Steven McLachlan

Background: L-Arginine (Arg) is an essential amino acid and a precursor for the synthesis of vascular nitric oxide, while L-Citrulline is a non-essential amino acid substrate for increasing L-arginine. Both L-arginine and L-Citrulline in translational studies may acutely lower the blood pressure. Current meta-analysis for L-arginine or L-Citrulline interventions in blood pressure have identified significant heterogeneity. Clinical trial evidence for L-arginine or L-Citrulline in chronic blood pressure reduction in the general population requires an examination of trial designs, as not all translational studies may have influenced vascular reactivity. Our aims are to explore whether L-arginine and L-citrulline intervention trials in chronic blood pressure consider standardized end points relevant to the general adult populations. Methods: A step-wise search on clinicaltrials.gov, the U.S. Library of Medicine registry for clinical trials, was performed including the following keyword search parameters: “completed” “L-Citrulline” “L-arginine” trial”, and “adults”, involving “blood pressure” reduction as a primary end point in adult humans. Results: Of the forty-four completed trials, only five were included for analysis. Following the careful evaluation of trial design, we observed heterogeneity across participant inclusion criteria (population sample size, age range, sex), interventional design (dosages, duration), and primary outcomes, measured with respect to changes in diastolic or systolic blood pressure. Conclusion: In conclusion, there is a lack of robust trial design evidence to suggest that L-arginine or L-Citrulline, based on current RCTs in the general population, have an overall positive effect on vascular endothelial reactivity and a beneficial chronic blood pressure-lowering effect. Indeed, conclusions drawn from human meta-analysis studies have been heterogenous between studies, which may be attributed to study design heterogeneity, including differences in sample population, age, and blood pressure at the time of entry. Inconsistencies in the study design poses a challenge for systematic reviews and meta-analysis to accurately assess the effect size and impact of L-arginine or L-citrulline on both systolic and diastolic blood pressure.