l-arginine vs l-citrulline

[newguy]

Br J Nutr. 2008 Apr;99(4):855-62. Epub 2007 Oct 22.Click here to read Links
Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study.

Previous experimental studies have highlighted that citrulline (CIT) could be a promising pharmaconutrient. However, its pharmacokinetic characteristics and tolerance to loading have not been studied to date. The objective was to characterise the plasma kinetics of CIT in a multiple-dosing study design and to assess the effect of CIT intake on the concentrations of other plasma amino acids (AA). The effects of CIT loading on anabolic hormones were also determined. Eight fasting healthy males underwent four separate oral loading tests (2, 5, 10 or 15 g CIT) in random order. Blood was drawn ten times over an 8 h period for measurement of plasma AA, insulin and growth hormone (Gh). Urine samples were collected before CIT administration and over the next 24 h. None of the subjects experienced side effects whatever the CIT dose. Concerning AA, only CIT, ornithine (ORN) and arginine (ARG) plasma concentrations were affected (maximum concentration 146 (sem to 303 (sem 11) micromol/l (ARG) and 81 (sem 4) to 179 (sem 10) micromol/l (ORN); time to reach maximum concentration 1.17 (sem 0.26) to 2.29 (sem 0.20) h (ARG) and 1.38 (sem 0.25) to 1.79 (sem 0.11) h (ORN) according to CIT dose). Even at high doses, urinary excretion of CIT remained low ( < 5 %). Plasma insulin and Gh were not affected by CIT administration. Short-term CIT administration is safe and well-tolerated. CIT is a potent precursor of ARG. However, at the highest doses, CIT accumulated in plasma while plasma ARG levels increased less than expected. This may be due to saturation of the renal conversion of CIT into ARG

- http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=1789836

This could start to give us an idea of potential dosing of l-citrulline.

[newguy]

L-Arginine Supplementation in Peripheral Arterial Disease

No Benefit and Possible Harm
Andrew M. Wilson, MBBS, PhD; Randall Harada, MD; Nandini Nair, MD, PhD; Naras Balasubramanian, PhD; John P. Cooke, MD, PhD From the Division of Cardiovascular Medicine (A.M.W., R.H., N.N., J.P.C.) and Department of Biostatistics (N.B.), Stanford University School of Medicine, Stanford, Calif.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University Medical Center, Falk Cardiovascular Research Institute, 300 Pasteur Dr, Stanford, CA 94305. E-mail john.cooke@stanford.edu

Received December 20, 2006; accepted May 3, 2007.

Background— L-Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. L-Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of L-arginine on vascular reactivity and functional capacity in patients with PAD.

Methods and Results— The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral L-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-Arginine supplementation significantly increased plasma L-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both L-arginine- and placebo-treated patients, the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024).

Conclusions— In patients with PAD, long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. As opposed to its short-term administration, long-term administration of L-arginine is not useful in patients with intermittent claudication and PAD.

- http://www.ncbi.nlm.nih.gov/pubmed/17592080

Hmm, this one isn't too promising.

[newguy]

Well, the studies show that L-arginine will raise the levels of serum arginine too. However, the question is does it stimulate arginase, and by that collagen products and by-products. That seems to be the implication. Since L-Arginine has dual fates (arginase to collagen and proline; versus NO synthase to NO - a BIG difference in fate!), I think the more important factoid is that it "does not induce tissue arginase".

Right now I have about 500 gm of L-arginine sitting on my shelf.

Tim

Yes, perhaps the safer option would be to take l-citrulline. Either that or with l-arginine be sure to take Norvaline to block arginase activity.

[Tim468]

Well, the studies show that L-arginine will raise the levels of serum arginine too. However, the question is does it stimulate arginase, and by that collagen products and by-products. That seems to be the implication. Since L-Arginine has dual fates (arginase to collagen and proline; versus NO synthase to NO - a BIG difference in fate!), I think the more important factoid is that it "does not induce tissue arginase".

Right now I have about 500 gm of L-arginine sitting on my shelf.

Tim

[newguy]

so what does this mean with larginine for those of us who are not doctors and who dont fully understand that document - do we keep taking it or what? ive just ordered another 4 bottles of it

I have loads of l-arginine too . I'm just toying with the prospect that l-citrulline may be as, if not more useful at raising NO levels. By all means keep taking the l-arginine you have.

[Iceman]

so what does this mean with larginine for those of us who are not doctors and who dont fully understand that document - do we keep taking it or what? ive just ordered another 4 bottles of it

[newguy]

Do you have a title or NHLBI reference?

Thanks, Tim

http://cat.inist.fr/?aModele=afficheN&cpsidt=19984543


Plus I found some more interesting studies:

Cardiovasc Drug Rev. 2006 Fall-Winter;24(3-4):275-90.
Therapeutic use of citrulline in cardiovascular disease.
L-citrulline is the natural precursor of L-arginine, substrate for nitric oxide synthase (NOS) in the production of NO. Supplemental administration L-arginine has been shown to be effective in improving NO production and cardiovascular function in cardiovascular diseases associated with endothelial dysfunction, such as hypertension, heart failure, atherosclerosis, diabetic vascular disease and ischemia-reperfusion injury, but the beneficial actions do not endure with chronic therapy. Substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea by arginase makes oral delivery (or l-arginine) very ineffective. Additionally, all of these disease states as well as supplemental L-arginine enhance arginase expression and activity, thus reducing the effectiveness of L-arginine therapy. In contrast, L-citrulline is not metabolized in the intestine or liver and does not induce tissue arginase, but rather inhibits its activity. L-citrulline entering the kidney, vascular endothelium and other tissues can be readily converted to L-arginine, thus raising plasma and tissue levels of L-arginine and enhancing NO production. Supplemental L-citrulline has promise as a therapeutic adjunct in disease states associated with L-arginine deficiencies.
http://www.ncbi.nlm.nih.gov/pubmed/17214603

A study in humans has shown that oral administration of L-citrulline at 3.8 g/m2 body
surface, resulted in a 227% peak increase in plasma L-arginine levels at 4 h, compared
with a 90% peak increase with the same dose of L-arginine (43). Furthermore, the area
under the curve plot of L-arginine plasma concentration vs. time was 3 fold larger for L-
citrulline, and the elevation in L-arginine levels was more persistent following L-citrulline
administration. Thus, acute oral administration of L-citrulline appears to be considerably
more efficient raising plasma levels of L-arginine than L-arginine itself. Additionally, a
recent study in children and young adults showed that five oral doses of L-citrulline every
12 hours (1.9 g/m2/dose) for a total dose of 9.5 g/m2 resulted in 57 and 85% increases in
mean plasma levels of L-arginine and L-citrulline, respectively (78). - http://jtcs.ctsnetjournals.org/cgi/reprint/132/1/58.pdf

For the final study, I found the text above and ha to search for the actual study. The pdf is a fairly large document called "Nitric oxide precursors and congenital heart surgery" and it appears to backup the above claims.

[Tim468]

Do you have a title or NHLBI reference?

Thanks, Tim

[newguy]

A couple of years old, but of interest.

AIMS
Oral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects.

  
METHODS
In a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects.

  
RESULTS
L-Citrulline dose-dependently increased AUC and Cmax of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the Cmin of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 ± 8 (baseline) to 278 ± 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 ± 10 to 125 ± 15 µmol mmol−1 creatinine (P = 0.01, 95% CI 8, 58) and from 38 ± 3.3 to 50 ± 6.7 nmol mmol−1 creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD.

  
CONCLUSION
Our data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.