Whole-body and intracellular arginine metabolism in hypertension: role of disease severity and sex

Background Arginine, as precursor of the antihypertensive metabolite nitric oxide, may influence blood pressure (BP) regulation and is therefore linked to hypertension, a serious global health issue. Thus, we investigated whether hypertension relates to alterations in arginine metabolism and examined the role of biological sex and body composition. Methods We stratified 762 older adults (50-95yo) participating in the MEDIT-trial into four BP groups (normal, elevated, stage 1 and 2 hypertension) per 2025 ACC/AHA guidelines. Body composition was assessed by Dual-energy X-ray absorptiometry. After administering stable tracers of arginine, citrulline, and ornithine, blood samples were taken to measure postabsorptive plasma amino acid concentrations and tracer enrichments by LC-MS/MS. Compartmental modeling was applied to determine amino acid kinetics. Results Age and glucose, hs-CRP, and arginine levels were comparable across groups. Older adults with stage 1 and stage 2 hypertension had higher BMIs than those with normal BP (29.7 kg/m2 and 31.0 kg/m2 vs. 27.8 kg/m2). Whole-body and intracellular arginine production in stage 2 hypertension were increased by 10.4% and 10.7% compared to those with normotension (all: P < .05), particularly in females (whole-body: +13.7%; intracellular: +18.3%; all: P < .02). While females showed progressive increases in body composition parameters along BP groups, males displayed relatively stable values. Conclusions Arginine metabolism in older adults is influenced by hypertension severity, with sex-specific differences in metabolic adaptation. Further research is warranted determining whether hypertension treatment for older adults should be individualized to disease severity, accounting for the upregulated arginine metabolism and sex-specific differences, which may lead to improved outcomes. Clinical Trial Registry www.clinicalTrials.gov, NCT01787682, NCT01871350, NCT01624792, NCT01890824, NCT02082418, NCT02157844, NCT06801964, NCT02065141, NCT03159390, NCT02770092, NCT02908425, NCT02780219, NCT02780206, NCT03327181, NCT06801951, NCT03796455, NCT04928872, NCT04461236, NCT05395390, NCT05240885, NCT06628349=