madman
Super Moderator
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.
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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