Arginine-Citrulline Sustain 120 tablets - enhances blood flow | Jarrow Formulas

Jarrow Formulas Arginine-citrulline Sustain™ supports Nitric Oxide production and enhances blood flow.

what does Arginine-Citrulline Sustain do? 
Jarrow Formulas Arginine-Citrulline Sustain is a synergistic combination of two amino acids to support nitric oxide (NO) production, blood flow and cardiovascular health.
L-Citrulline largely converts to L-Arginine, increasing circulating and blood vessel levels of L-Arginine for NO production.
Arginine-Citrulline Sustain provides these amino acids to the body over an 8 hour period.

benefits
• reduces muscle fatigue
• increases nitrogen oxide (NO) which leads to vasodilation and results into the famous 'pump'
• a higher NO production also results in higher muscle synthesis as NO also stimulates formation of muscle protein

background reading
The amino acid L-arginine is required for the enzymatic synthesis of the messenger molecule nitric oxide (NO) in the body. The vascular endothelium is a single layer of cells between the blood vessel lumen and underlying vascular smooth muscle cells. NO produced by vascular endothelial cells is essential for the proper function of blood vessels and maintenance of cardiovascular health.

Nitric Oxide & vascular function
Once synthesized, NO diffuses across the endothelial cell membrane and enters the vascular smooth muscle cells to modulate tone (constriction/dilation). NO is a potent vasodilator, allowing blood vessels to relax and widen to enhance blood flow. The balance between NO and various endothelium-derived vasoconstrictors and the sympathetic nervous system maintains blood vessel tone. NO also suppresses platelet aggregation (blood clotting), immune cell adhesion to the blood vessel surface, vascular permeability, and blunts vascular smooth muscle cell migration and proliferation.

NO bioactivity is determined by the balance between its synthesis and degradation. Reduced NO bioactivity due to diminished production and/or enhanced degradation manifests as impaired endotheliumdependent vasodilation (endothelial dysfunction). Endothelial nitric oxide synthase (eNOS), the endothelial isoform of the enzyme, utilizes the amino acid L-arginine and molecular oxygen to produce NO in the process giving rise to a related amino acid, L-citrulline, as a byproduct.
Research indicates endothelial dysfunction results from selective impairment of the L-arginine-NO pathway with endothelial dysfunction rather than from reduced responsiveness of vascular smooth muscle cells to NO signaling.

Oral arginine limitations
Oral L-arginine bioavailability to support endothelial NO synthesis is low due to extensive metabolism to urea by the enzyme arginase in the intestines and liver (~80%). Arginase competes with eNOS for their common substrate arginine. High levels of circulating L-arginine induce arginase activity in the liver, kidney, and vasculature, which increases arginine degradation. Even though most ingested L-arginine is metabolized in the intestines and liver, levels that reach systemic circulation are sufficient to augment vascular arginase activity to limit availability for endothelial NO production. Levels and activity of arginase are increased with aging and various conditions characterized by oxidative stress and impaired vascular function.

Citrulline substitute
L-citrulline is an important substitute for L-arginine under certain physiologic conditions that limit L-arginine availability as it because citrulline serves as substrate for de novo synthesis of L-arginine in mammals. Oral supplementation with L-citrulline is more effective than L-arginine in raising blood arginine levels because it largely bypasses metabolism in the gut and liver. Unlike L-arginine, L-citrulline is not a substrate for, nor does it induce, arginase activity, so exhibits remarkably high systemic bioavailability. Ingested L-citrulline is primarily metabolized to L-arginine by the kidney, releasing arginine equivalent to ~75% of the L-citrulline taken up.
Endothelial cells can also convert L-citrulline back to L-arginine to provide the requisite substrate for NO production.
Oral citrulline supplementation has been shown to dose-dependently raise blood arginine levels in healthy adults more efficiently than equivalent doses of arginine. Of note, citrulline is scarce in the diet, with the only notable source, watermelon, providing 0.7 – 3.6 mg per gram. Thus, levels consumed naturally through the diet without supplementation may be too low to significantly increase blood arginine levels.

Dynamic duo
Recent scientific evidence has shown the combination of arginine and citrulline in a 1:1 ratio more rapidly and effectively increases blood levels of L-arginine compared to either individual amino acid ingested alone (2, 3). L-citrulline suppresses arginase activity, acting as a noncompetitive (allosteric) inhibitor, so is anticipated to spare arginine from first-pass metabolism in the intestines and liver to make oral L-arginine more available to the vascular endothelium to support NO production.
Additionally, the utilization of oral arginine for NO synthesis was higher with a sustained- compared to an immediate-release L-arginine preparation in people with endothelial dysfunction, despite similar blood levels of arginine. A slow arginine absorption rate may limit activation of the metabolic disposal of arginine to favor its use in other metabolic pathways, including eNOS-mediated NO synthesis.

Oxidative stress & Nitric Oxide bioactivity
Oxidative stress reduces NO bioactivity, so is causally linked to impaired vascular function. Tetrahydrobiopterin (BH4) is an essential eNOS cofactor required for NO synthesis. In its active, reduced form, BH4 is highly susceptible to oxidation. Diminished BH4 availability compromises eNOS function by promoting electron transfer to molecular oxygen instead of L-arginine to generate superoxide radical (O2−) instead of NO. This phenomenon is commonly referred to as “eNOS uncoupling.” Uncoupled eNOS may initiate a vicious feedforward cycle to propagate oxidative stress that further increases oxidative degradation of NO and BH4, progressive eNOS uncoupling, and impaired vascular function. BH4 deficiency plays a major role in impaired vascular function.

Vitamin C to the rescue
Antioxidant vitamin C discourages eNOS uncoupling under conditions of oxidative stress by stabilizing BH4. Supplementation with vitamin C has been shown to prevent oxidation of BH4 and thereby to facilitate eNOS-derived NO production. Evidence also suggests that vitamin C enhances eNOS activity independent of BH4 stabilization through alterations in eNOS phosphorylation that increase enzymatic activity