Coop's Corner #2: L-Norvaline?


L-Norvaline has been advertised for several years as an arginase inhibitor, capable of preventing the degradation of arginine. This is thought to increase NO levels by virtue of increased arginine availability as a precursor to nitric oxide.

Today we will look at what L-Norvaline will and will not do in healthy men.

L-norvaline is a mixed arginase inhibitor, meaning that it degrades arginine not only in the liver (the site of urea production), but also various other locations including the GI lumen and endothelium of vasculature.

To date, every study showing that norvaline was effective in improving vascular parameters was conducted in unhealthy populations: be it metabolic syndrome, hypertension, or diabetes. The common denominator in all these cases is vascular inflammation and subsequent endothelial dysfunction.

Without getting too sciency, here are some passages worth reading:

"In conditions of normally functioning endothelium, the balance between vasoconstriction and vasodilatation factors is supported. The basic vasodilatation agent in endothelium is NO. Infringement of the given balance leads to development of endothelial dysfunction. L-arginine serves as a source of NO in a cell. Inhibitors of arginase, suppressing activity of the given enzyme, promote NO biosynthesis increase, preventing the development of endothelial dysfunction. Application of L-norvaline promotes suppression of activity of arginase enzyme which allows for a raise in L-arginine stocks."

Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction

"Emerging evidence suggests that increased endothelial arginase activity decreases L-arginine availability for eNOS to produce NO under various pathological conditions [17]. The arginase inhibitor L-norvaline has been previously shown to improve endothelial NO release via inhibition of arginase [18]. Treatment of ApoE-/- mice with arginase inhibitors has been reported to improve endothelial function and reduce plaque formation [19]. It is however, not clear whether arginase is indeed involved in vascular inflammation responses, a crucial mechanism in atherogenesis. The present study further investigated whether arginase is involved in the modulation of endothelial inflammatory responses and whether this is dependent on NOS activity in endothelial cells. In cultured human endothelial cells, we demonstrate that the arginase inhibitor L-norvaline exerts anti-inflammatory effect at the same concentration ranges which exhibit arginase inhibitory activity [18]."

Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline

What this is essentially saying is that people with endothelial dysfunction end up overexpressing arginase, which not only depletes the body of the arginine necessary for the NO/cGMP pathway, but it also seems to be involved in inflammation and atherogenesis. This is effectively an arginine deficiency. Norvaline ameliorates this deficiency by taking the activity of the arginase enzyme back to normal levels.

Unfortunately, a similar effect would not be expected in healthy humans, wherein arginase expression is adequate and further reduction in endothelial arginase will prove worthless due to a lack of concomitant increases in eNOS expression. Furthermore, the anti-inflammatory effect of norvaline on the endothelium will be absent since healthy individuals should not have signs of atherosclerosis to begin with.

In fact, supplementing with norvaline (at high doses) may be detrimental to health, as norvaline has demonstrated to reduce arginase expression in hepatocytes. Arginase is a key enzyme in ridding the body of nitrogenous waste. It catalyzes the last step of urea production. Urea is primarily how nitrogen is removed from the human body. If you inhibit hepatic arginase to a strong enough degree, there is potential for hyperammonemia due to negative feedback loops in the urea cycle, which often result in psychotic symptoms. Indeed, we see this with the rare care of congenital arginase deficiency.

Lastly, norvaline may be able to inhibit arginase activity in the GI lumen. This is the sole potential utility that I see for norvaline in a healthy human. By inhibiting arginase activity in the lumen, it is possible that more ingested arginine will reach the plasma. Unfortunately, the same issue with eNOS expression holds true, and arginine has repeatedly failed to raise NO in healthy human subjects. Arginine may have other benefits, again seen primarily in cases of metabolic disorders.

So the verdict on Norvaline?

Low doses won't do anything, high doses may be detrimental to health, and medium doses co-ingested with arginine may increase arginine's bioavailability.

The story changes completely if you have endothelial dysfunction.

Stay tuned for round 3 next time I take a good stimulant dose :D

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