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Magic gas molecule, in the atmosphere it is a noxious chemical, but in the body in small controlled doses it is extraordinarily beneficial.
Nitric oxide (NO) consists of one atom of nitrogen and one atom of oxygen. It is one of the smallest molecules in nature with a molecular weight of 30 Daltons. Nitric oxide is synthesized by many different cell types and it controls or influences a number of important physiologic processes. An intriguing aspect of the NO molecule is that it can both mediate normal physiological events and be highly toxic.
How it works:
NO functions as a signaling molecule that tells the body to make blood vessels relax and widen. This physiological reaction is important when the body needs more blood. NO works as a signaling molecule in the cardiovascular system, the nervous system, and in other tissues,.
The primary determinant of which NO affects biological systems or centers depends on its chemistry. The chemical effect of NO in biological systems is extensive and complex, it is divided into two major categories, direct and indirect:
Direct effect are defined as those reactions fast enough to occur between NO and specific biological molecules. Indirect effects do not involve NO, but rather are mediated by reactive nitrogen oxide species (RNOS) formed from the reaction of NO either with oxygen or superoxide. RNOS formed from NO can mediate either nitrosative or oxidative stress.
Synthesis
Nitric oxide is produced by many different cell types including vascular endothelium, neuronal cells, macrophages, and white blood cells. Nitric oxide synthesis involves arginine, oxygen, and nicotinamide adenine dinucleotide phosphate (NADPH). The enzyme nitric oxide synthase (NOS) facilitates the synthesis of NO from the guanidino nitrogen in the L-arginine molecule; Larginine is converted to NO and L-citrulline in a two-step process.
NOSs, is a family of related enzymes encoded by separate genes. NOS is one of the most regulated enzymes in biology. There are three known isoforms, two are constitutive (cNOS) and the third is inducible (iNOS). Cloning of NOS enzymes indicates that, cNOS include both brain constitutive (NOS1) and endothelial constitutive (NOS3), the third is the inducible (NOS2) gene.
Neuornal Endothelial
Constitutive Nitric Oxide Synthase NOS1 (b cNOS) Neuornal Residing at 12q24.2 Comprises 28 exons extend over 100kb.
NOS3 (e cNOS) Endothelial Residing at 7q35-7q36 Comprises 26 exons that span 21kb.
Under normal, basal conditions in blood vessels, NO is continually being produced by cNOS. The activity of cNOS is calcium and calmodulin dependent. By the mid-1980 Furchgott and others identified endothelium-derived relaxing factor (EDRF) as being NO. iNOS. It differs, in part, from cNOS in that its activation is calcium independent. Under normal, basal conditions, the activity of iNOS is very low. The activity of iNOS is stimulated during inflammation by bacterial endotoxins (e.g., lipopolysaccharide) and cytokines such as tumor necrosis factor (TNF) and interleukins. During inflammation, the amount of NO produced by iNOS may be a 1,000-fold greater than that produced by cNOS.
NOS oxidizes the quanidine group of L-arginine in a process that consumes five electrons and results in the formation of NO with stoichiometric formation of L-citrulline. The process involves the oxidation of NADPH and the reduction of molecular oxygen. The transformation occurs at a catalytic site adjacent to a specific binding site of L-arginine. The NO formed diffuses out of its cells of origin and into nearby target cells, where it binds to the heme group of cytosolic guanylate cyclase and thereby causes enzyme activation. This interaction represents a novel and widespread signal transduction mechanism that link extracellular stimuli to the synthesis of cyclic GMP in nearby target cells.
NO is of great clinical importance; it is becoming increasingly obvious that it is an important physiological and pathophysiological factor. NO is an important messenger molecule involved in many physiological and pathological processes within the mammalian body both beneficial and detrimental. Appropriate levels of NO production are important in protecting an organ such as the liver from ischemic damage. However sustained levels of NO production result in direct tissue toxicity and contribute to the vascular collapse associated with septic shock, whereas chronic expression of NO is associated with various carcinomas and inflammatory conditions including juvenile diabetes, multiple sclerosis, arthritis and ulcerative colitis,.
Physiological Role
The synthesis of NO by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure.
NO also contributes to the control of platelet aggregation and the regulation of cardiac contractility.
In the central nervous system NO is a neurotransmitter that underlines several functions including the formation of memory. In the periphery, there is a widespread network of nerves, previously recognized as nonadrenergic and noncholinergic, that operate through a NO dependent mechanism to mediate some forms of neurogenic vasodilatation and regulate various gastrointestinal, respiratory, and genitourinary tract functions.
NO must be handled with extreme caution. On contact with air NO interacts with O2, producing a dimeric form of nitrogen dioxide, a reddish brown gas. Inhalation of 25 ppm of mixed nitrogen oxide, the recommended threshold limit, may cause pulmonary irritation. Higher doses of NO may cause minimal irritation initially but result in hemorrhagic pulmonary edema several days later. Levels as low as 100 ppm are dangerous and 200 ppm may be lethal. Individuals exposed to nitrogen oxide should be carefully monitored and receive supportive care, including supplemental O2, morphine and steroid therapy.
NO Donors
Currently, exogenous NO sources constitute a powerful way to supplement NO when the body can not generate enough for normal biological functions. (novel NO donors, NO releasing devices).
NITRIC OXIDE
Important messenger molecule involved in many pathological and physiological processes within the mammalian body both beneficial and detrimental. NO has a potent antimicrobial and antiviral activity against wide array of organisms. NO is also mediating endothelial cell growth, contributing to DNA damage and carcinogenesis, NO is promoting angiogenesis. ..
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