Nitric Oxide and Nitric Oxide Synthase
Nitric oxide formed from L-arginine appears to be present in all cells in the body and is believed essential in a number of important homeostatic processes. In blood NO is rapidly inactivated by oxyhemoglobin to form methemoglobin. While NO normally has a very short half-life of only 3–5 seconds, some of the NO formed in vivo can survive 30–40 times longer if reacted with nitroso adducts on albumin. Most of the biological effects of NO are mediated via the activation of soluble guanylyl cyclase which increases cyclic-GMP in cells. However, some NO-mediated effects are guanylyl cyclase independent.
The production of NO from L-arginine occurs by way of NO synthase (NOS). Three isoforms of NOS exist: inducible (iNOS), endothelial (eNOS), and neuronal (nNOS). Normally levels of L-arginine are in the millimolar range. As the Km (half saturation concentration) for NOS is in the micromolar range, one would predict that NOS should be saturated with its substrate L-arginine, and that additional L-arginine should not affect NO production. However, under various pathologic conditions L-arginine has been shown to increase NO and influence physiological function, and thus this “arginine paradox” has been the subject of much investigation. One explanation that has gained the most interest is the finding that high levels (2–10 times normal) of the endogenous L-arginine analog asymmetric dimethyl-L-arginine (ADMA) are present during many of these pathologic conditions and can inhibit NOS.2 The formation of ADMA is not from circulating free L-arginine, but appears to derive from the posttranslational methylation of peptide bound arginine in proteins (e.g., histones, heat shock proteins).3 Elevated ADMA, shown to be capable of inhibiting NOS, has been reported in renal failure, hypertension, preeclampsia, hypercholesterolemia, tobacco use, diabetes mellitus, and aging.4 Supplemental L-arginine is capable of competing with ADMA and overcoming this inhibitory effect.5 Elevations in cholesterol and associated atherogenic lipoproteins or glucose decrease the major catabolic enzyme involved in ADMA metabolism. This enzyme, dimethylarginine dimethylaminohydrolase (DDAH) is significantly decreased (40%–60%) in animals fed high-cholesterol diets or given streptozotocin which experimentally induces diabetes mellitus and hyperglycemia.6 The resulting disruption of ADMA metabolism by DDAH may explain the underlying dysregulation of NO synthesis in endothelial cells in various pathologic conditions.
An additional pathway involving the nonenzymatic synthesis of NO has been proposed, in which L-arginine combines with the highly reactive oxygen species hydrogen peroxide or superoxide anion to yield NO. This pathway may help to explain why L-arginine has been shown to be effective in some conditions characterized by oxidative stress.
Tissue injury and repair increases the demand for L-arginine.7 While initially there is a decrease in L-arginine and a corresponding increase in L-citrulline and NO in the injured tissue, during the repair period L-arginine continues to be depleted as L-ornithine production increases due to the action of arginase.
L-Arginine can undergo numerous metabolic fates. In addition to its role as a component of most proteins, this amino acid can be converted to urea, L-citrulline, L-ornithine, L-proline, L-glutamate, and polyamines such as putrescine. Creatine, the high-energy phosphate storage form found in skeletal muscles, is also formed from L-arginine. Recently the decarboxylation of L-arginine via L-arginine decarboxylase to form agmatine has been reported. Agmatine may act as an endogenous antihypertensive agent, similar in mechanism to that of clonidine. Thus L-arginine plays an important role in the body’s response to injury.
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Nitric oxide formed from L-arginine appears to be present in all cells in the body and is believed essential in a number of important homeostatic processes. In blood NO is rapidly inactivated by oxyhemoglobin to form methemoglobin. While NO normally has a very short half-life of only 3–5 seconds, some of the NO formed in vivo can survive 30–40 times longer if reacted with nitroso adducts on albumin. Most of the biological effects of NO are mediated via the activation of soluble guanylyl cyclase which increases cyclic-GMP in cells. However, some NO-mediated effects are guanylyl cyclase independent.
The production of NO from L-arginine occurs by way of NO synthase (NOS). Three isoforms of NOS exist: inducible (iNOS), endothelial (eNOS), and neuronal (nNOS). Normally levels of L-arginine are in the millimolar range. As the Km (half saturation concentration) for NOS is in the micromolar range, one would predict that NOS should be saturated with its substrate L-arginine, and that additional L-arginine should not affect NO production. However, under various pathologic conditions L-arginine has been shown to increase NO and influence physiological function, and thus this “arginine paradox” has been the subject of much investigation. One explanation that has gained the most interest is the finding that high levels (2–10 times normal) of the endogenous L-arginine analog asymmetric dimethyl-L-arginine (ADMA) are present during many of these pathologic conditions and can inhibit NOS.2 The formation of ADMA is not from circulating free L-arginine, but appears to derive from the posttranslational methylation of peptide bound arginine in proteins (e.g., histones, heat shock proteins).3 Elevated ADMA, shown to be capable of inhibiting NOS, has been reported in renal failure, hypertension, preeclampsia, hypercholesterolemia, tobacco use, diabetes mellitus, and aging.4 Supplemental L-arginine is capable of competing with ADMA and overcoming this inhibitory effect.5 Elevations in cholesterol and associated atherogenic lipoproteins or glucose decrease the major catabolic enzyme involved in ADMA metabolism. This enzyme, dimethylarginine dimethylaminohydrolase (DDAH) is significantly decreased (40%–60%) in animals fed high-cholesterol diets or given streptozotocin which experimentally induces diabetes mellitus and hyperglycemia.6 The resulting disruption of ADMA metabolism by DDAH may explain the underlying dysregulation of NO synthesis in endothelial cells in various pathologic conditions.
An additional pathway involving the nonenzymatic synthesis of NO has been proposed, in which L-arginine combines with the highly reactive oxygen species hydrogen peroxide or superoxide anion to yield NO. This pathway may help to explain why L-arginine has been shown to be effective in some conditions characterized by oxidative stress.
Tissue injury and repair increases the demand for L-arginine.7 While initially there is a decrease in L-arginine and a corresponding increase in L-citrulline and NO in the injured tissue, during the repair period L-arginine continues to be depleted as L-ornithine production increases due to the action of arginase.
L-Arginine can undergo numerous metabolic fates. In addition to its role as a component of most proteins, this amino acid can be converted to urea, L-citrulline, L-ornithine, L-proline, L-glutamate, and polyamines such as putrescine. Creatine, the high-energy phosphate storage form found in skeletal muscles, is also formed from L-arginine. Recently the decarboxylation of L-arginine via L-arginine decarboxylase to form agmatine has been reported. Agmatine may act as an endogenous antihypertensive agent, similar in mechanism to that of clonidine. Thus L-arginine plays an important role in the body’s response to injury.
"The Grow Taller Guys"
Learn how this STIMULANT TO GROW TALLER has helped many grow taller and faster.