Citrulline the new star for increasing nitric oxide

madman

Member
Endogenous flux of nitric oxide: Citrulline is preferred to Arginine





Abstract


Both arginine (Arg) and its precursor citrulline (Cit) have received much interest during the past two decades because of their potential effects on whole-body nitric oxide (NO) production and augmentation of NO-dependent signaling pathways. However, the usefulness of Arg supplementation for NO production is questionable due to its high splanchnic first-pass metabolism (FPM), which limits its systemic availability. Both hepatic- and extra-hepatic arginases critically limit the availability of Arg for the NO synthase enzymes (NOSs) and therefore, a limited amount of oral Arg can reach the systemic circulation for NO synthesis. Arg has also some undesired effects including induction of arginase activity, an increase of urea levels, a decrease of cellular uptake of Cit, and a decrease of the recycling of Arg from Cit. In contrast, Cit has more availability as an NO precursor because of its high intestinal absorption, low FPM, and high renal reabsorption. At the cellular level, the co-localization of Cit transport systems and the enzymes involved in the Cit-Arg-NO pathway facilitates channeling of Cit into NO. Furthermore, cells preferably use Cit rather than either intra- or extra-cellular Arg to improve NO output, especially in high-demand situations. In conclusion, available evidence strongly supports the concept that Cit leads to higher NO production and suggests that Cit may have a better therapeutic effect than Arg for NO-disrupted conditions.





1. Introduction

Arginine (Arg), a conditionally essential amino acid, has received significant research interest over the last two decades, because of its involvement in several metabolic pathways 1. Although Arg has key roles in the synthesis of proteins, creatine, polyamines, agmatine, and urea, as well as in the metabolism of proline and glutamate in the body 1, the focus has been on its capability as a unique precursor of nitric oxide (NO) 2. This property has led to its widely used as a complementary treatment in various NO-disrupted conditions such as hypertension 3-5, preeclampsia 6, and endothelial dysfunction 7. Despite lack of direct evidence, some effects of Arg supplementation on NO-related functions, for example, regulation of blood pressure and vascular function, has led to a dominant paradigm that oral administration increases its systemic availability and promotes NO production. This notion has now been challenged because there is strong evidence indicating limited bioavailability of orally ingested Arg 8,9, its plasma and cellular compartmentalization, and the competitive pathways utilizing Arg for the synthesis of urea and ornithine 10,11.

Citrulline (Cit) is a neutral, non-essential, non-protein amino acid, which is an intermediary in the urea cycle, and also a precursor of Arg de novo synthesis and NO production 12. Currently, Cit is receiving much attention as a natural NO precursor, especially for its potential cardiovascular and anti-hypertensive benefits and also for enhancing exercise performance and recovery 13-17. This is because Arg supplementation is not as effective as Cit for NO production 18 and has some undesirable effects including induction of arginase activity 19,20, increase urea levels 21, a decrease in cellular uptake of Cit 22, decrease in the recycling of Arg form Cit 20, suppression of eNOS expression and activity 23, and induction of cellular oxidative stress 23. In addition, there is some evidence suggesting the existence of cellular “Arg tolerance” following long-term Arg exposure, a phenomenon that reduces the expected beneficial effects of long-term Arg supplementation 23. Furthermore, there is some debate regarding the efficacy 24 and safety 25 of long-term Arg supplementation, for example, an increased risk of myocardial infarction and mortality rate has been reported following supplementation of 9 g/d of Arg for 6 months. 25 There are also numerous reports supporting the efficacy and safety of Cit 13,26,27 thus highlighting the importance of Cit as a precursor of Arg and NO. In this review, we summarize the evidence suggesting that supplementation with Cit is superior over Arg itself to improve Arg systemic bioavailability and NO production. If Cit is unequivocally shown to be superior over Arg as a safe and effective precursor for endogenous NO production, then its supplementation will receive further justification in medical practice.





Conclusion


As summarized in Table 2, current evidence indicates the preference for Cit over Arg administration for NO production. Because of more efficient intestinal absorption, low FPM, and high renal reabsorption, oral Cit compared with the same dose of Arg provides more systemic available Arg in a sustainable manner. Cit is a more powerful NO precursor than Arg because: (1) exogenous Cit increases intracellular Arg pools, (2) Cit transporters and ASS-ASL enzymes are co-localized and coinduced with NOS enzymes, and (3) Cit recycling pathway is found in NO-producing cells. In contrast, imported Arg seems to be more available for arginase rather than the NOSs, which effectively limits its accessibility for NO synthesis and shuttles Arg into other cellular pathways (e.g., production of ornithine and polyamines). The evidence strongly supports the hypothesis that extracellular sources of Arg can be utilized for other cellular requirements than NO production. On the other hand, side-effects (e.g., induction of arginase, disruption of ADMA metabolism, and inhibition of Cit recycling pathway), inhibit the usefulness of Arg supplementation for NO production. Since Cit is superior over Arg as a safe and effective precursor of NO production, its supplementation has further justification in medical practice.
 

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madman

Member
FIGURE 1 A, Determinants of Arg plasma flux and Arg catabolic pathways. Both exogenous (10-30%) and endogenous sources (60-90%) contribute to Arg plasma flux. A large fraction of Arg flux is diverted into arginase I and urea cycle (50% by hepatic and 15% by extrahepatic arginase I); 10-30% of Arg fraction is utilized for the synthesis of creatine (using l-arginine: glycine amidinotransferase; AGAT), and only a minor fraction is shuttled into NO production. B, Cit flux is supported mainly by the endogenous sources. The intestinal biosynthesis of Cit provides 60-90% of Cit flux and is mainly supported by the conversion of glutamine to Cit. Extraintestinal synthesis accounting for 10-30% of Cit flux, is mainly relayed on both the Cit-NO cycle and the ADMA-DDAH pathway. Cit flux is entirely used for Arg production via both renal and non-renal ASS-ASL pathways. ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase. Arg, Arginine; Cit, Citrulline, Gln, glutamine, Pro, proline
Screenshot (2315).png
 

madman

Member
FIGURE 2 Overview of Cit-NO cycle. ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; DDAH, dimethylarginine dimethylaminohydrolase; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase; ADMA, asymmetric dimethylarginine; CPS, carbamoyl phosphate synthetase; NO, nitric oxide; NOS, NO synthase; Arg, arginine; Cit, citrulline; NOHA, N(G)- hydroxy-L-arginine.
Screenshot (2316).png
 

madman

Member
FIGURE 3 The fate of orally ingested doses of Arg. Ingested Arg is extracted and utilized during the first-pass metabolism of the splanchnic region (intestinal and hepatic bed); Arg entered in the enterocytes is mainly confined into the partial urea cycle by both cytosolic and mitochondrial arginases to produce urea, ornithine, Cit, proline, polyamines, and CO2. The Arg delivered into the liver by the portal vein, is subjected to further catabolism via arginase I and is mainly converted to urea; within the splanchnic metabolism, a minor fraction of the ingested dose of Arg is converted to NO. Finally, about 10-30% of ingested doses are available for circulation; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase; GS, glutamine synthetase
Screenshot (2320).png
Screenshot (2321).png
 

madman

Member
FIGURE 4 Arginine pools and cellular compartments of Cit transporters with NOSs and Cit utilizing enzymes (ASS-ASL). Extracellular Arg can only support intracellular Arg pool-I, which is accessible by iNOS rather than eNOS. Other Arg pools (pool-IIA and pool-IIB) are not freely exchangeable with extracellular space and are supported by intracellular synthesized Arg via ASS-ASL; these pools are therefore dependent on extracellular Cit or Cit recycled by Cit-NO cycle and ADMA-DDAH pathway. The effective compartment of CAT-1 and CAT-2B with eNOS and ASS-ASL makes extracellular Cit an available source of NO production. ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; PRMTs, protein arginine methyltransferases; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase.
Screenshot (2322).png
 

Nelson Vergel

Founder, ExcelMale.com


 

Nelson Vergel

Founder, ExcelMale.com
 

wondering

Active Member
Anyone see a rise in creatinine levels when taking L-Citrulline or Arginine? My creatinine is at the upper limit and the data I have seen shows it tends to increase it. Yet, low NO2 is bad for CVD and low NO2 is present in all levels of CKD. So, hmm...now what?
 
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Vince

Super Moderator
Anyone see a rise in creatinine levels when taking L-Citrulline or Arginine? My creatinine is at the upper limit and the data I have seen shows it tends to increase it. Yet, low NO2 is bad for CVD and low NO2 is present in all levels of CKD. So, hmm...now what?
No, L-Citrulline doesn't increase creatinine levels. Of course, working out before your labs, will increase creatinine levels. You may need to skip your workouts, 48 hours before labs.
 

DorianGray

Active Member
The dietary application of L-arginine is the basic determinant of the L-arginine level in plasma, as the biosynthesis of L-arginine is not able to balance inadequate intake or deficiency. Providing supplementation of substrate to individuals with inadequate NO, therefore, has been suggested as a rational approach to NO production by the NO synthase, provided the enzyme is functional an the protein complex (as mentioned above-ASL, partial urea cycle). The problem is the protein pathway integrity is suspect in those that exhibit NO or endothelial compromise. Perhaps lump festering cardiovascular problems and ED sufferers in this group. So, it makes one wonder to what extent Citrulline would be processed in the shunt to make even exogenous supplementation effective. The protein complex, ASA, ASL,and NOS reveals that cells use intracellular pools of L-citrulline, which is then converted to L-arginine, rather than utilizing extracellular L-arginine to make NO. On a more critical note, research has shown L-arginine supplementation had demonstrated increase mortality in post-myocardial infarction patients and worsening of conditions in those with peripheral artery disease (PAD). Boger RH. L-arginine therapy in cardiovascular pathologies...Curr Opin Clin Nutr Metab Care. 2008;11 (1):55-61, Erez A, et al, Requirementof arginosuccinate lyase for systemic nitric oxide production. Nat Med. 2011;17(12):1619-26.
 

mg707

New Member
Anyone see a rise in creatinine levels when taking L-Citrulline or Arginine? My creatinine is at the upper limit and the data I have seen shows it tends to increase it. Yet, low NO2 is bad for CVD and low NO2 is present in all levels of CKD. So, hmm...now what?
I supplement with L-Arginine and I'm at the higher end of creatine too, but I also drink BANG energy drinks and they have a lot of creatinine in them. Check your supplements and energy drinks, they may contain creatinine
 

wondering

Active Member
I supplement with L-Arginine and I'm at the higher end of creatine too, but I also drink BANG energy drinks and they have a lot of creatinine in them. Check your supplements and energy drinks, they may contain creatinine

Creatine and creatinine are NOT the same thing.
 

mg707

New Member
True but the levels of both are highly correlated. Creatinine is the waste byproduct when your muscles break down creatine. High levels of creatine can lead to high levels of Creatinine, but isn’t always the driver
 

Nelson Vergel

Founder, ExcelMale.com
If you are taking creatine and your creatinine increases enough to freak out your doctor, ask him to run this test:

 

Test-Joe

New Member
Anyone see a rise in creatinine levels when taking L-Citrulline or Arginine? My creatinine is at the upper limit and the data I have seen shows it tends to increase it. Yet, low NO2 is bad for CVD and low NO2 is present in all levels of CKD. So, hmm...now what?
Yes! I regularly used both for pre-workout 3-4 week. However, I recently retired and working out most days using L-Citrulline and Arginine as pre-work supplement. Bloodwork in July (before retiring) creatinine levels were within normal limits, but on the upper range of normal. Recent labs after retiring showed creatinine levels above normal and had jumped 0.3 points since July. Also my GFR (indicator of renal function) had fallen below normal. Primary Care Provider was concerned and thought it was my Test dosage. However, that was unchanged from July. Only connection I could make was the increase usage of the two supplements. I have reduced the amount I am using each workout and will recheck labs in March.
 

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