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=.