L-arginine supplementation improved by cytosolic calcium maintenance

In this study, researchers from the University of New England in Maine explored the metabolic link that is responsible for AMPK functional modulation during continuous L-arginine exposure. The results of their study were published in the journal Nutrition Research.

• Continuous dosing leads to the loss of therapeutic benefits associated with short-term L-arginine supplementation.
• The functional modulation of AMP-activated protein kinase (AMPK) correlates with the therapeutic effectiveness of L-arginine and with the development of tolerance during continuous supplementation.
• The researchers incubated HUVECs for seven days with 100 micromoles per liter (umol/L) L-arginine in the presence or absence of other agents.
• They monitored their effects for eNOS function and on tolerance sparing (cellular glucose accumulation and oxidative stress).
• They reported that HUVEC co-incubation with L-arginine and ?1200 milligrams per milliliter (mg/mL) calcium (Ca2+) for seven days prevented tolerance development, with an increase in eNOS and AMPK functional activity, and overall cellular glucose uptake.
• The overall cellular cytosolic Ca2+was below 200 nanomoles per liter (nmol/L) with no change in cellular glucose and superoxide/peroxynitrite (O2•?/ONOO?) level from control.
• The researchers observed at least 70 percent decrease in eNOS and AMPK functional response, with a reduction in glucose uptake, and an increase in O2•?/ONOO? in cells exposed for seven days to L-arginine at Ca2+co-incubation concentration of >1200 mg/mL.
• The >1200 mg/mL Ca2+ co-incubation condition also improved the overall cellular Ca2+to >200 nmol/L.
• The researchers observed a similar tolerance response in cells co-treated with L-arginine and ?1200 mg/mL Ca2+ in the presence of Ca2+ influx inhibitor (20 umol/L 1,2-bis(o-aminophenoxy)ethane-N,N,N?,N?-tetra acetic acid), or eNOS activity inhibitor (30 umol/L l-NG-nitroarginine methyl ester).
• They did not observe a tolerance response in cells incubated for seven days with L-arginine and ?1200 mg/mL Ca2+, even in the presence of the inhibitor for cellular glucose induction (30 umol/L 5-chloro-2-(n-(2,5-dichlorobenzenesulfonamide))-benzoxazole).

The researchers concluded that maintaining cytosolic Ca2+ within a threshold limit of less than 200 nmol/L is necessary to extend the therapeutic efficacy of L-arginine during continuous dosing, without any potential tolerance development.

Journal Reference:

Mohan S, Harding L. MAINTENANCE OF CYTOSOLIC CALCIUM IS CRUCIAL TO EXTEND L-ARGININE THERAPEUTIC BENEFITS DURING CONTINUOUS DOSING. Nutrition Research. October 2016;36(10):1114–1120. DOI: 10.1016/j.nutres.2016.07.002