Oral supplementation with L‐homoarginine in young volunteers

Abstract

Keywords asymmetric dimethylarginine, L-arginine, L-homoarginine, nitric oxide, vascular function AIMSLow blood concentrations of the naturally occurring amino acid L-homoarginine (L-hArg) are related to impaired cardiovascular outcome and mortality in humans and animals. L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro. The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation. METHODSIn a double-blind, randomized, placebo-controlled crossover study, 20 young volunteers received 125 mg L-hArg once daily for 4 weeks. Kinetic parameters (C max , T max and AUC 0-24h ) were calculated after ingestion of single and multiple doses of oral supplementation as primary endpoint. Secondary endpoints that were evaluated were routine laboratory, L-arginine, asymmetric dimethylarginine (ADMA), pulse wave velocity (PWV), augmentation index (AIx), flow-mediated vasodilatation (FMD), corticospinal excitability, i.e. motor threshold (MT), and cortical excitability, i.e. intracortical inhibition (ICI) and facilitation (ICF). RESULTSOne hour after ingestion (T max ), L-hArg increased the baseline L-hArg plasma concentration (2.87 ± 0.91 μmol l À1 , mean ± SD) by 8.74 ± 4.46 [95% confidence intervals 6.65; 10.9] and 17. 3 ± 4.97 [14.9; 19.6] μmol l À1 (C max ), after single and multiple doses, respectively. Once-only and 4 weeks of supplementation resulted in AUCs 0-24h of 63. 5 ± 28.8 [50.0; 76.9] and 225 ± 78.5 [188; 2624] μmol l À1 *h, for single and multiple doses, respectively. Routine laboratory parameters, L-arginine, ADMA, PWV, AIx, FMD, MT, ICI and ICF did not change by L-hArg supplementation compared to baseline. CONCLUSIONOnce daily orally applied 125 mg L-hArg raises plasma L-hArg four-and sevenfold after single dose and 4 weeks of supplementation, respectively, and is safe and well tolerated in young volunteers. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• L-Homoarginine (L-hArg) is an amino acid found in pea pulses (Lathyrus sativus and cicera). It is a weak substrate for nitric oxide (NO) synthases (NOS) and an inhibitor of arginases.• In clinical and epidemiological studies, low circulating L-hArg is associated with impaired cerebrovascular and cardiovascular outcome.• Orally administered L-hArg is readily absorbed in rats and pigs with a recovery of >95% of unmetabolized L-hArg in urine. WHAT THIS STUDY ADDS• Our data show that oral supplementation with 125 mg L-hArg raises plasma L-hArg concentrations four-and sevenfold after single and multiple dosing in humans, respectively.• Four weeks of supplementation did not change vascular and neuronal function in young volunteers, nor did any toxic side-effects occur.

Homoarginine and all‐cause mortality: A systematic review and meta‐analysis

“…Although homoarginine supplementation studies have been generally conducted in animals, Atzler et al 44 have recently demonstrated the feasibility and safety of acute and chronic oral homoarginine supplementation in humans. Although homoarginine supplementation studies have been generally conducted in animals, Atzler et al 44 have recently demonstrated the feasibility and safety of acute and chronic oral homoarginine supplementation in humans.…”

“…Pending confirmation in further studies, the strong and independent association observed between circulating homoarginine concentrations and mortality not only suggests that homoarginine might represent a novel biomarker of risk but also raises the possibility that interventions affecting homoarginine concentrations might favourably affect clinical outcomes. Although homoarginine supplementation studies have been generally conducted in animals, Atzler et al 44 have recently demonstrated the feasibility and safety of acute and chronic oral homoarginine supplementation in humans. In this study, homoarginine supplementation, 125 mg/d, was associated with a significant increase in plasma homoarginine concentrations (baseline concentration: 2.87 AE 0.91 lmol/L; C max after a single dose: 8.74 AE 4.46 lmol/L; C max after 4 weeks: 17.3 AE 4.97 lmol/L).…”

The prognostic biomarker L-homoarginine is a substrate of the cationic amino acid transporters CAT1, CAT2A and CAT2B

“…Moreover, the IC 50 -values are far above the physiological plasma concentration of L-homoarginine 5, 16 . All this makes a significant interference of oral L-homoarginine supplementation with cellular uptake of L-arginine and NOS synthesis unlikely.…”

Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications

“…Although mouse studies revealed a causal link between hArg and vascular disease, the direct protective effect in humans remains to be established [107]. In a recent clinical trial, pharmacokinetic and -dynamic parameters were studied in healthy volunteers orally supplemented with 125mg hArg or placebo daily for 4 weeks using a cross-over design [108]. Supplementation was well tolerated and increased hArg levels by 7 fold without any alteration of vascular or neurological parameters [108,109].…”

“…In a recent clinical trial, pharmacokinetic and -dynamic parameters were studied in healthy volunteers orally supplemented with 125mg hArg or placebo daily for 4 weeks using a cross-over design [108]. Supplementation was well tolerated and increased hArg levels by 7 fold without any alteration of vascular or neurological parameters [108,109]. Currently, a randomized placebo-controlled trial studies the administration of oral hArg in acute stroke patients with low hArg levels (https://www.clinicaltrials.gov; unique identifier: NCT03692234).…”