madman
Super Moderator
Abstract
As a functional amino acid (AA), L-arginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine in mammals (including humans). NO (a major vasodilator) increases blood flow to tissues. Arg and its metabolites play important roles in metabolism and physiology. Arg is required to maintain the urea cycle in the active state to detoxify ammonia. This AA also activates cellular mechanistic target of rapamycin (mTOR) and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, promoting spermatogenesis and sperm quality, improving conceptus survival and growth, and augmenting the production of milk proteins. Although Arg is formed de novo from glutamine/glutamate and proline in humans, these synthetic pathways do not provide sufficient Arg in infants or adults. Thus, humans and other animals do have dietary needs of Arg for optimal growth, development, lactation, and fertility. Much evidence shows that oral administration of Arg within the physiological range can confer health benefits to both men and women by increasing NO synthesis and thus blood flow in tissues (e.g., skeletal muscle and the corpora cavernosa of the penis). NO is a vasodilator, a neurotransmitter, a regulator of nutrient metabolism, and a killer of bacteria, fungi, parasites, and viruses [including coronaviruses, such as SARS-CoV and SARS-CoV-2 (the virus causing COVID19). Thus, Arg supplementation can enhance immunity, anti-infectious, and anti-oxidative responses, fertility, wound healing, ammonia detoxification, nutrient digestion and absorption, lean tissue mass, and brown adipose tissue development; ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension); and treat individuals with erectile dysfunction, sickle cell disease, muscular dystrophy, and pre-eclampsia.
10.1 Introduction
L-arginine (Arg) is a basic amino acid (AA) present in the physiological fluids of humans. This nutrient is required for the synthesis of protein and other low-molecular-weight substances, including nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine (Bollenbach et al. 2019; Tsai and Kass 2009; Wu and Morris 1998). The oxidation of one guanidino nitrogen of Arg by NO synthase (NOS) to generate NO occurs in virtually all mammalian cells, including endothelial cells, macrophages, neuronal cells, muscle cells, adipocytes, enterocytes, and renal epithelial cells (Stuehr et al. 2001). Three distinct isoforms of NOS [neuronal NOS (nNOS; NOS1), inducible NOS (iNOS; NOS2), and endothelial NOS (eNOS; NOS3)] have been identified. They are encoded by different genes and differ in molecular, catalytic, and immunological properties, cellular distribution, regulation of activity, and sensitivity to inhibitors (Alderton et al. 2001). All NOS isoforms require tetrahydrobiopterin (BH4), NADPH, FAD, FMN, and heme for NO synthesis (Fig. 10.1), whereas eNOS and nNOS also require calcium and calmodulin for their enzymatic activities (Förstermann and Sessa 2012). Available evidence shows that NO synthesis in mammals is regulated by dietary factors (Wu and Meininger 2002). For example, Arg, taurine, polyunsaturated fatty acids, calcium, vitamin C, phytoestrogens, and polyphenols stimulate, while glutamine, lysine, saturated fatty acids, fructose, cholesterol, and homocysteine inhibit, NO synthesis by eNOS and nNOS (Wu and Meininger 2002). This illustrates the complexity of NO production and has important implications for understanding the responses of humans to dietary Arg supplementation with regard to NO production by specific cells and the whole body. The main objective of this article is to highlight the role of Arg in NO synthesis and health in humans.
10.2 The Arg Paradox in Mammalian NO Synthesis
10.3 Physiological Functions of Arg and NO in Mammals
10.4 Dietary Requirements of Humans for Arg for Optimal Health
10.5 Determination of NO Synthesis by Cells and WholeBody NO Synthesis
10.6 Effects of Oral Arg Supplementation on NO Production in Humans
10.7 Effects of Oral Arg Supplementation on Enhancing Blood Flow to Skeletal Muscle in Humans
10.8 Effects of Oral Arg Supplementation on Enhancing Blood Flow to the Corpora Cavernosa of the Penis
*NO relaxes the smooth muscle of corpora cavernosa in the penis, thereby contributing to the development and maintenance of an erection of the penis (Rajfer et al. 1992). There are reports that oral Arg supplementation enhanced blood flow to the corpora cavernosa of the penis. For example, in a randomized, double-blind, placebo-controlled study, 46 men with confirmed organic erectile dysfunction received oral administration of either 5 g Arg/day or placebo for 6 weeks (Chen et al. 1999). The amount of Arg or placebo was divided into three equal doses daily. Before and after the study, the patients completed a questionnaire related to sexual drive, erectile function, and overall sexual satisfaction. Results indicated that 31% of patients taking the Arg supplement reported a significant subjective improvement in erectile function (Chen et al. 1999). Interestingly, all the patients who reported subjective improvements initially had low urinary excretion of nitrite plus nitrate; and the values had doubled by the end of the study. Thus, dietary Arg supplementation may be more effective for ameliorating erectile dysfunction in patients with alterations in the endothelial Arg-NO pathway and a reduction in vascular NO availability.
In another study, 15 impotent men received oral administration of 2.8 g/day Arg or placebo (microcrystalline cellulose) for a 2-week period (Zorgniotti and Lizza 1994). The placebo was given first. The patients were asked to keep a diary of their sexual behavior. Forty percent of men (6/15) in the treatment group reported improvement in erectile function, compared to none in the placebo group (0/15). The positive responders were younger and had a better penile vascular structure than the non-responders. In support of this finding of improved erectile function, a meta-analysis of 10 different studies with a total of 540 patients indicated that oral administration of 1.5–5 g Arg could improve erectile function, as compared with the placebo group (Rhim et al. 2019). Likewise, dietary supplementation with 1.5 g L-citrulline per day augmented erectile hardness in patients with mild erectile dysfunction. As previously mentioned, L-citrulline can be converted into Arg for the synthesis of NO. These participants were given 1.5 g L-citrulline per day, and researchers noted that the supplement was safe and psychologically well-tolerated by the study participants, while improving their sexual function (Cormio et al. 2011). Similar results have been reported for oral administration of Arg plus Pycnogenol (an extract isolate from the French maritime pine bark; containing antioxidants such as procyanidins, bioflavonoids, and phenolic acids) or a combination of Arg, L-citrulline, Pycnogenol, and roburins [belonging to a class of tannins known as ellagitannins (antioxidants) that can be metabolized by intestinal bacteria to generate bioactive molecules called urolithins (Stanislavov and Rohdewald 2015)]. Thus, dietary supplementation with Arg or L-citrulline alone or in combination with other bioactive substances may be beneficial for treating erectile dysfunction in men.
10.9 Effects of Oral Arg Supplementation on Alleviating Oxidative Stress and Associated Vascular Complications in Human Diseases
10.10 Effects of Oral Arg Supplementation on Enhancing Immunity in Humans and Mitigating the Current Global COVID-19 Pandemic
10.11 L-Citrulline as an Effective Precursor of Arg in Humans
In humans, L-citrulline is synthesized de novo from glutamine/glutamate and proline in their enterocytes (Wu and Morris 1998). It is worthy to note that L-citrulline can successfully replace Arg for treating patients affected by the impaired absorption of Arg (e.g., humans with lysinuric protein intolerance) (Kamada et al. 2001). L-citrulline does not share the same transporter with Arg across the plasma membrane and the intracellular conversion of L-citrulline into Arg consumes ammonia in the form of aspartate (Wu and Meininger 2000). In mammals (including humans), L-citrulline is effectively used for Arg synthesis by the kidneys, endothelial cells, macrophages, smooth muscle cells, and other cell types (Wu and Morris 1998). Thus, urinary Lcitrulline excretion accounts for <1% of the citrulline load (0.18 g/kg BW/day) filtered by kidneys in healthy adults (Rougé et al. 2007). Citrulline supplementation may be a more effective way to increase Arg concentration in plasma and the whole-body NO status, for example, in SCD, because L-citrulline is readily converted into Arg within cells. Furthermore, our studies with rats, pigs, and sheep have shown that L-citrulline has a much longer half-life than Arg in the blood, and exogenously administered L-citrulline can sustain elevated concentrations of Arg in the plasma for a much longer period than exogenously administered Arg (Lassala et al. 2009; Wu 2021). This may also be true for humans.
10.12 Conclusion
In summary, humans have dietary requirements for Arg to meet functional needs, because this AA is inadequately synthesized in the body. There are myths about Arg nutrition in humans due to both insufficient knowledge and severely confounded results from inadequately designed clinical experiments (including inappropriate controls and small sample size). Compelling evidence shows that oral administration of Arg within the physiological range can confer benefits in increasing NO synthesis in the vasculature, blood flow to muscles, and sexual function in humans. Furthermore, dietary supplementation with Arg can enhance immune and anti-oxidative responses, as well as gastrointestinal and pulmonary functions, ammonia detoxification, fertility, embryonic survival, wound healing, brown adipose tissue development, fatty acid, and glucose oxidation, and lean tissue mass. Arg supplementation can beneficially ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension) and treat patients with SCD, muscular dystrophy, and preeclampsia. Finally, Arg-derived NO can kill pathogens, including the virus that causes COVID-19. The scientific evidence available to date supports the notion that Arg or L-citrulline offers promise in improving the health and wellbeing of both men and women.
As a functional amino acid (AA), L-arginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine in mammals (including humans). NO (a major vasodilator) increases blood flow to tissues. Arg and its metabolites play important roles in metabolism and physiology. Arg is required to maintain the urea cycle in the active state to detoxify ammonia. This AA also activates cellular mechanistic target of rapamycin (mTOR) and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, promoting spermatogenesis and sperm quality, improving conceptus survival and growth, and augmenting the production of milk proteins. Although Arg is formed de novo from glutamine/glutamate and proline in humans, these synthetic pathways do not provide sufficient Arg in infants or adults. Thus, humans and other animals do have dietary needs of Arg for optimal growth, development, lactation, and fertility. Much evidence shows that oral administration of Arg within the physiological range can confer health benefits to both men and women by increasing NO synthesis and thus blood flow in tissues (e.g., skeletal muscle and the corpora cavernosa of the penis). NO is a vasodilator, a neurotransmitter, a regulator of nutrient metabolism, and a killer of bacteria, fungi, parasites, and viruses [including coronaviruses, such as SARS-CoV and SARS-CoV-2 (the virus causing COVID19). Thus, Arg supplementation can enhance immunity, anti-infectious, and anti-oxidative responses, fertility, wound healing, ammonia detoxification, nutrient digestion and absorption, lean tissue mass, and brown adipose tissue development; ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension); and treat individuals with erectile dysfunction, sickle cell disease, muscular dystrophy, and pre-eclampsia.
10.1 Introduction
L-arginine (Arg) is a basic amino acid (AA) present in the physiological fluids of humans. This nutrient is required for the synthesis of protein and other low-molecular-weight substances, including nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine (Bollenbach et al. 2019; Tsai and Kass 2009; Wu and Morris 1998). The oxidation of one guanidino nitrogen of Arg by NO synthase (NOS) to generate NO occurs in virtually all mammalian cells, including endothelial cells, macrophages, neuronal cells, muscle cells, adipocytes, enterocytes, and renal epithelial cells (Stuehr et al. 2001). Three distinct isoforms of NOS [neuronal NOS (nNOS; NOS1), inducible NOS (iNOS; NOS2), and endothelial NOS (eNOS; NOS3)] have been identified. They are encoded by different genes and differ in molecular, catalytic, and immunological properties, cellular distribution, regulation of activity, and sensitivity to inhibitors (Alderton et al. 2001). All NOS isoforms require tetrahydrobiopterin (BH4), NADPH, FAD, FMN, and heme for NO synthesis (Fig. 10.1), whereas eNOS and nNOS also require calcium and calmodulin for their enzymatic activities (Förstermann and Sessa 2012). Available evidence shows that NO synthesis in mammals is regulated by dietary factors (Wu and Meininger 2002). For example, Arg, taurine, polyunsaturated fatty acids, calcium, vitamin C, phytoestrogens, and polyphenols stimulate, while glutamine, lysine, saturated fatty acids, fructose, cholesterol, and homocysteine inhibit, NO synthesis by eNOS and nNOS (Wu and Meininger 2002). This illustrates the complexity of NO production and has important implications for understanding the responses of humans to dietary Arg supplementation with regard to NO production by specific cells and the whole body. The main objective of this article is to highlight the role of Arg in NO synthesis and health in humans.
10.2 The Arg Paradox in Mammalian NO Synthesis
10.3 Physiological Functions of Arg and NO in Mammals
10.4 Dietary Requirements of Humans for Arg for Optimal Health
10.5 Determination of NO Synthesis by Cells and WholeBody NO Synthesis
10.6 Effects of Oral Arg Supplementation on NO Production in Humans
10.7 Effects of Oral Arg Supplementation on Enhancing Blood Flow to Skeletal Muscle in Humans
10.8 Effects of Oral Arg Supplementation on Enhancing Blood Flow to the Corpora Cavernosa of the Penis
*NO relaxes the smooth muscle of corpora cavernosa in the penis, thereby contributing to the development and maintenance of an erection of the penis (Rajfer et al. 1992). There are reports that oral Arg supplementation enhanced blood flow to the corpora cavernosa of the penis. For example, in a randomized, double-blind, placebo-controlled study, 46 men with confirmed organic erectile dysfunction received oral administration of either 5 g Arg/day or placebo for 6 weeks (Chen et al. 1999). The amount of Arg or placebo was divided into three equal doses daily. Before and after the study, the patients completed a questionnaire related to sexual drive, erectile function, and overall sexual satisfaction. Results indicated that 31% of patients taking the Arg supplement reported a significant subjective improvement in erectile function (Chen et al. 1999). Interestingly, all the patients who reported subjective improvements initially had low urinary excretion of nitrite plus nitrate; and the values had doubled by the end of the study. Thus, dietary Arg supplementation may be more effective for ameliorating erectile dysfunction in patients with alterations in the endothelial Arg-NO pathway and a reduction in vascular NO availability.
In another study, 15 impotent men received oral administration of 2.8 g/day Arg or placebo (microcrystalline cellulose) for a 2-week period (Zorgniotti and Lizza 1994). The placebo was given first. The patients were asked to keep a diary of their sexual behavior. Forty percent of men (6/15) in the treatment group reported improvement in erectile function, compared to none in the placebo group (0/15). The positive responders were younger and had a better penile vascular structure than the non-responders. In support of this finding of improved erectile function, a meta-analysis of 10 different studies with a total of 540 patients indicated that oral administration of 1.5–5 g Arg could improve erectile function, as compared with the placebo group (Rhim et al. 2019). Likewise, dietary supplementation with 1.5 g L-citrulline per day augmented erectile hardness in patients with mild erectile dysfunction. As previously mentioned, L-citrulline can be converted into Arg for the synthesis of NO. These participants were given 1.5 g L-citrulline per day, and researchers noted that the supplement was safe and psychologically well-tolerated by the study participants, while improving their sexual function (Cormio et al. 2011). Similar results have been reported for oral administration of Arg plus Pycnogenol (an extract isolate from the French maritime pine bark; containing antioxidants such as procyanidins, bioflavonoids, and phenolic acids) or a combination of Arg, L-citrulline, Pycnogenol, and roburins [belonging to a class of tannins known as ellagitannins (antioxidants) that can be metabolized by intestinal bacteria to generate bioactive molecules called urolithins (Stanislavov and Rohdewald 2015)]. Thus, dietary supplementation with Arg or L-citrulline alone or in combination with other bioactive substances may be beneficial for treating erectile dysfunction in men.
10.9 Effects of Oral Arg Supplementation on Alleviating Oxidative Stress and Associated Vascular Complications in Human Diseases
10.10 Effects of Oral Arg Supplementation on Enhancing Immunity in Humans and Mitigating the Current Global COVID-19 Pandemic
10.11 L-Citrulline as an Effective Precursor of Arg in Humans
In humans, L-citrulline is synthesized de novo from glutamine/glutamate and proline in their enterocytes (Wu and Morris 1998). It is worthy to note that L-citrulline can successfully replace Arg for treating patients affected by the impaired absorption of Arg (e.g., humans with lysinuric protein intolerance) (Kamada et al. 2001). L-citrulline does not share the same transporter with Arg across the plasma membrane and the intracellular conversion of L-citrulline into Arg consumes ammonia in the form of aspartate (Wu and Meininger 2000). In mammals (including humans), L-citrulline is effectively used for Arg synthesis by the kidneys, endothelial cells, macrophages, smooth muscle cells, and other cell types (Wu and Morris 1998). Thus, urinary Lcitrulline excretion accounts for <1% of the citrulline load (0.18 g/kg BW/day) filtered by kidneys in healthy adults (Rougé et al. 2007). Citrulline supplementation may be a more effective way to increase Arg concentration in plasma and the whole-body NO status, for example, in SCD, because L-citrulline is readily converted into Arg within cells. Furthermore, our studies with rats, pigs, and sheep have shown that L-citrulline has a much longer half-life than Arg in the blood, and exogenously administered L-citrulline can sustain elevated concentrations of Arg in the plasma for a much longer period than exogenously administered Arg (Lassala et al. 2009; Wu 2021). This may also be true for humans.
10.12 Conclusion
In summary, humans have dietary requirements for Arg to meet functional needs, because this AA is inadequately synthesized in the body. There are myths about Arg nutrition in humans due to both insufficient knowledge and severely confounded results from inadequately designed clinical experiments (including inappropriate controls and small sample size). Compelling evidence shows that oral administration of Arg within the physiological range can confer benefits in increasing NO synthesis in the vasculature, blood flow to muscles, and sexual function in humans. Furthermore, dietary supplementation with Arg can enhance immune and anti-oxidative responses, as well as gastrointestinal and pulmonary functions, ammonia detoxification, fertility, embryonic survival, wound healing, brown adipose tissue development, fatty acid, and glucose oxidation, and lean tissue mass. Arg supplementation can beneficially ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension) and treat patients with SCD, muscular dystrophy, and preeclampsia. Finally, Arg-derived NO can kill pathogens, including the virus that causes COVID-19. The scientific evidence available to date supports the notion that Arg or L-citrulline offers promise in improving the health and wellbeing of both men and women.
