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Under normal conditions, Gln and Arg are nonessential amino acids. But it seems likely that Cholesterol intake increases demand for both Gln & Arg and consequently endogenous Gln and Arg supplies become a limiting factor for cholesterol metabolic processes; for this reason, in the subjects that have high cholesterol intake or even those who are prone to develop hypercholesterolemia, Gln and Arg are essential nutrients. Gln & Arg supplements should be administered in combination and should consider the dose carefully and according to clinical trial. Introduction Arg (2-amino-5-guanidinovaleric acid) is an amino acid that serves many heart-healthy functions. Evidence suggests that Arg may help regulate cholesterol levels [1]. 

Besides, Arg appears to act as a natural blood thinner by reducing platelet aggregation hypercholesterolemic humans [2]. It may also preserve the elasticity of blood vessels through antioxidant actions. In addition, L-Arg is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system, Nitric oxide is a molecule of gas that penetrates cells and regulates their functioning, and can help to control blood pressure, which the body uses to keep blood vessels dilated, allowing the heart to receive adequate oxygen. [3, 4] Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis [5]. 

Rabbits fed high cholesterol diet have increased leukocyte adhesion, which prevented by L-Arg supplementation. Platelets derived from hypercholesterolemic patients and rabbits show in vitro an enhanced tendency to aggregate [2, 6]. It has been demonstrated that L-Arg, the substrate of endogenous NO synthase, reverses the enhanced platelet aggregation in hypercholesterolemia in vitro suggests that reduced production or bioavailability of NO is involved in hypercholesterolemia-induced thromboembolic processes [2, 6]. 

In addition, L-Arg also improves endothelium-dependent vasodilatation in humans with hypercholesterolemia and atherosclerosis, given to patients with early stages of heart disease arginine prevents the disease from getting worse and relieves chest pain and improves clinical symptoms of cardiovascular disease in man [7]. It has been demonstrated that administration of L-Arg can improve endothelium-dependent vascular relaxation through the release of NO [5]. Recent studies suggest an interaction between l-Arg and l-Gln in the control of nitric oxide (NO) synthesis. These results suggested that Gln is an essential amino acid for NO synthesis by macrophages and raise the strong possibility that Gln acts with nitric oxide synthase to catalyze the conversion of Arg to NO. 

The consumption of Gln during sepsis may represent NO production. [8,9]. Further, there is a relation between cholesterol level and the ratio of non-essential amino acids to essential amino acids in plasma, while plasma levels of essential amino acids have been found to be elevated in hyperlipidaemic patients [10]. It has been shown that hypercholesterolemic diets caused significant changes in plasma free amino acid concentrations in human subjects [11]. The results of our previous study indicated that there are correlation between feeding some pure L-essential amino acids and cholesterol level in rabbit and rat [12, 13] Our recent results show that feeding of young rats with cholesterol for 20 weeks significantly increased the Arg content of the kidney whereas it almost depleted contents of free Gln in the liver and the kidney tissues in the treated animal groups ( 14) Some investigators suggested that the beneficial effects of glutamine (15, 16) mediated by increased Arg production in the kidney in rats (17), as well as in humans (15). 

Thus, it seems possible that there is a correlation between the cholesterol intake and Gln in the kidney and in the liver and consequently with arginine production. Under normal physiological circumstances, glutamine is a nonessential amino acid. It has been postulated that, under conditions of increased demand, endogenous glutamine supplies can become a limiting factor for metabolic processes; for this reason, glutamine is sometimes referred to as a conditionally essential amino acid [18, 19]. 

However, like glutamine, arginine has been hypothesized to be a conditionally essential amino acid because alterations in its metabolism during catabolic states such as trauma and sepsis indicate that it may be essential under these conditions [20, 21]. Since the result of our study indicates that the endogenous of the two amino acids were subjected to the different alterations according to the tissues as a result of cholesterol intake, it seem likely that the chronic intake of cholesterol leads to an increase of the demands for Gln and Arg, under such conditions (increased intake of cholesterol) both of which may be considered as essential amino acids Indeed, Gln play many roles, including as a signal or regulator of metabolic demands [22]. 

In addition, L-glutamine is the most abundant free amino acid in the body (e.g., in plasma and skeletal muscle) [ 23] and yet is the most susceptible to depletion under such clinical conditions as sepsis, trauma, infection and inflammation [24], L-glutamine may play an important role in regulating NO synthesis and thus the function of the cardiovascular system [25, 26] On the other side the content of Arginine significantly elevated in the cardiac tissue of experimental group concomitant with a significant elevation in the content of Gln. These changes also were associated with significant reductions in these two amino acids in the remaining tissues. These alterations may have resulted from a selective increase in the transport of the affected amino acid from the tissues to the heart. 

Really, several mechanisms exist for the transport of amino acids across cell membranes. The Gamma glut amyl cycle is one example for the group transfer mechanism of amino acid transport. Such transport may result form activation of the enzyme gamma glutamyl transpeptidase (γGT) and glutathione both of which are present in the examined organs, which are implicated in amino acid transport across cell membranes [27]. This suggestion is in accordance with the finding that glutamine contributes significantly to glutathione synthesis [ 28, 29]. Administration of Gln into animal increased tissue [28] and plasma [29] glutathione concentrations. Indeed, glutathione is a crucial antioxidant found in high concentrations in the kidney, liver and other tissues [27]. 

Furthermore, Gln was found to be the precursor of L-Arg and thus nitric oxide synthesis in macrophages. [9, 30]. NO synthesis by endothelial cells increased with increasing extracellular L-arginine concentrations in the presence of L-Gln [31]. Our results also illustrate the changes in the contents of Gln and Arg in various tissues except liver and kidney are almost in the same directions. These results are in harmony with the recent studies which suggest an interaction between l-Arg and l- Gln in the control of nitric oxide (NO) synthesis: These results suggest that Gln is an essential amino acid for NO synthesis by macrophages and raise the strong possibility that Gln acts with nitric oxide synthase to catalyze the conversion of Arg to NO. [9, 30] Furthermore, endogenous L-Gln may play a regulatory role in the biosynthesis of endothelium-derived relaxing factor [32]. The biosynthesis of endothelium-derived relaxing factor not only produces a powerful vasodilator but also relieve the endothelial cell of excess nitrogen [32]. Indeed, the amino acid Gln plays a crucial role in nitrogen metabolism. 

In multicellular organisms, glutamine serves as the principal nitrogen carrier between cells [33], also, it was suggested that glutamine is a main nitrogen carrier in rats [34]. Arg is a key component of the nitric oxide pathway – and important cascade of reactions involved in vasodilatation and related to cardiovascular function. Arg supplements have been associated with reductions in symptoms associated with coronary artery disease and may be capable of slowing the progression of atherosclerosis (2,5and 6). In the body, Arg serves as the substrates for the nitric oxide synthase enzyme, which catalyzes the oxidation of Arg to produce citrulline and nitric oxide (NO) [35]. In people with elevated cholesterol levels, it is common to see a reduced ability of the endothelium to produce NO and, therefore, to dilate effectively. In addition, because NO production may be limited, blood cells such as monocytes and platelets are more likely to attach themselves to the inner vessel wall and lead to blockages [2, 6]. Arg supplements have been shown to restore endothelial vasodilatation in the coronary arteries of people with high cholesterol and reduce the ability of blood cells to adhere to the vessel walls. 

Improvements in coronary artery blood flow and reductions in myocardial ischemia [7, 36]. It has been reported that L-Glu as a possible precursor of L-Arg and thus nitric oxide synthesis [25]. Further it has suggested that glutamine metabolism has a physiological role in vascular function [26]. Indeed glutamine was found to be involved in the hepatic metabolism of lipids [37]. 6. 

CONCLUSIONS: Thus, a new line of evidence arose from these observations that the utilization of the two amino acids increases in response to high cholesterol intake, thus a combination of Gln and Arg may have pharmacologic and therapeutic implications in hypercholesterolemia. Under normal conditions, Gln and Arg are nonessential amino acids. But it seems likely that Cholesterol intake increase demand for both Gln & Arg and consequently endogenous glutamine and Arg supplies become a limiting factor for cholesterol metabolic processes; for this reason, in the subjects that have high cholesterol intake or even those who are prone to develop hypercholesterolemia, Gln and Arg are essential nutrients. Gln & Arg supplements should be administered in combination and should consider the dose carefully and according to clinical trial. 6. 

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