biological functions of nitric oxide biological functions of nitric oxide nitric oxide (nitrogen monoxide) is a molecule and chemical compound with chemical formula of no. in mammals including humans, nitric oxide is a signaling molecule involved in several physiological and pathological processes. it is a powerful vasodilator with a half-life of a few seconds in the blood. standard pharmaceuticals such as nitroglycerine and amyl nitrite are precursors to nitric oxide. low levels of nitric oxide production are typically due to ischemic damage in the liver. as a consequence of its importance in neuroscience, physiology, and immunology, nitric oxide was proclaimed "molecule of the year" in 1992. research into its function led to the 1998 nobel prize for elucidating the role of nitric oxide as a cardiovascular signalling molecule. sources of nitric oxide nitric oxide biosynthesis platelet-derived factors, shear stress, acetylcholine, and cytokines stimulate the production of no by endothelial nitric oxide synthase (enos). enos synthesizes no from the terminal guanidine-nitrogen of l-arginine and oxygen and yields citrulline as a byproduct. no production by enos is dependent on calcium-calmodulin and other cofactors. nitric oxide synthases (noss) synthesize the metastable free radical nitric oxide (no). three isoforms are known for the nos enzyme: endothelial (enos), neuronal (nnos), and inducible (inos) - each with separate functions. the neuronal enzyme (nos-1) and the endothelial isoform (nos-3) are calcium-dependent and produce low levels of this gas as a cell signaling molecule. the inducible isoform (nos-2) is calcium-independent and produces large amounts of gas that can be cytotoxic. nos oxidizes the guanidine 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. no is an important regulator and mediator of numerous processes in the nervous, immune, and cardiovascular systems. these include vascular smooth muscle relaxation, resulting in arterial vasodilation and increasing blood flow. no is also a neurotransmitter and has been associated with neuronal activity and various functions such as avoidance learning. no also partially mediates macrophage cytotoxicity against microbes and tumor cells. besides mediating normal functions, no is implicated in pathophysiologic states as diverse as septic shock, hypertension, stroke, and neurodegenerative diseases. pathway for nitrosylation of heme-thiolate, steps in cell signalling (porphyrin is depicted as the square). exogenous no (no-delivery drugs) exogenous no sources constitute a powerful way to supplement no when the body cannot generate enough for normal biological functions. certain endogenous compounds can act as no-donors or elicit no-like reactions in vivo. nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. the vasodilating antihypertensive drug minoxidil contains an ·no moiety and may act as an no agonist. likewise, sildenafil citrate, popularly known by the trade name viagra, stimulates erections primarily by enhancing signaling through the nitric oxide pathway. prominent examples are s-nitrosothiols, certain organic nitrates, nitrosylated metal complexes, dinitrosyl iron complexes (dnic), and even nitrite anions (no2− ) under hypoxic conditions a high salt intake attenuates no production in patients with essential hypertension, although bioavailability remains unregulated. other, including dietary dietary nitrate is also an important source of nitric oxide in mammals. green, leafy vegetables and some root vegetables (such as beetroot) have high concentrations of nitrate. when eaten and absorbed into the bloodstream, nitrate is concentrated in saliva (about 10-fold) and is reduced to nitrite on the surface of the tongue by a biofilm of commensal facultative anaerobic bacteria. this nitrite is swallowed and reacts with acid and reducing substances in the stomach (such as ascorbate) to produce high concentrations of nitric oxide. the purpose of this mechanism to create no is thought to be both sterilization of swallowed food (to prevent food poisoning) and to maintain gastric mucosal blood flow. the nitrate-nitrite-nitric oxide pathway elevates nitric oxide through the sequential reduction of dietary nitrate derived from plant-based foods. nitrate-rich vegetables, in particular leafy greens, such as spinach and arugula, and beetroot, have been shown to increase cardioprotective levels of nitric oxide with a corresponding reduction in blood pressure in pre-hypertensive persons. for the body to generate nitric oxide through the nitrate-nitrite-nitric oxide pathway, the reduction of nitrate to nitrite (by nitrate reductase, a bacterial enzyme) occurs in the mouth, by commensal bacteria, an obligatory and necessary step. monitoring nitric oxide status by saliva testing detects the bioconversion of plant-derived nitrate into nitric oxide. a rise in salivary levels is indicative of diets rich in leafy vegetables which are often abundant in anti-hypertensive diets such as the dash diet. a related mechanism is thought to protect the skin from fungal infections, where nitrate in sweat is reduced to nitrite by skin commensal organisms and then to no on the slightly acidic skin surface. in alternative fashion, nitrite anions on sun-exposed skin may be photolyzed to free nitric oxide radicals by uva in sunlight. this mechanism may elicit significant changes to the systemic blood circulation in humans and be exploited for therapeutic purposes. nasal breathing also produces nitric oxide within the body. immune response a dinitrosyl iron complex (dnic), the product from the immune responsive attack of no on fe-s proteins.nitric oxide is generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response. phagocytes are armed with inducible nitric oxide synthase (inos), which is activated by interferon-gamma (ifn-γ) as a single signal or by tumor necrosis factor (tnf) along with a second signal. on the other hand, transforming growth factor-beta (tgf-β) provides a strong inhibitory signal to inos, whereas interleukin-4 (il-4) and il-10 provide weak inhibitory signals. in this way, the immune system may regulate the armamentarium of phagocytes that play a role in inflammation and immune responses. nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including leishmania and malaria; the mechanism for this includes dna damage and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds. the inducible pathway (inos) of nitrogen oxide synthesis in phagocytes can generate large amounts of no that trigger apoptosis and kill other cells. in vitro studies indicate that phagocyte-dependent generation of no at concentrations greater than 400-500 nm triggers apoptosis in nearby cells and that this effect may act in a manner similar to specialized pro-resolving mediators to dampen and reverse inflammatory responses by neutralizing and then speeding the clearance of pro-inflammatory cells from inflamed tissues. however, the role of ·no in inflammation is complex with model studies involving viral infection suggesting that this gaseous mediator can also promote inflammation. in response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance. because nitric oxide might serve as an inflammometer (meter of inflammation) in conditions like asthma, interest has increased in the use of exhaled nitric oxide as a breath test in diseases with airway inflammation. reduced levels of exhaled no have been associated with exposure to air pollution in cyclists and smokers, but, in general, levels of exhaled nitric oxide are associated with exposure to air pollution. molecular effects of no on biological systems in cells, two broad classes of reactions of nitric oxide involve the s-nitrosation of thiols and the nitrosylation of some metalloenzymes. s-nitrosation of thiols s-nitrosation involves the (reversible) conversion of thiol groups, including cysteine residues in proteins, to form s-nitrosothiols (rsnos). s-nitrosation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein. nitrosylation of metal centers, especially iron nitric oxide to a transition metal ion like iron or copper, forming metal nitrosyl complexes. typical cases involve the nitrosylation of heme proteins like cytochromes, thereby disabling the normal enzymatic activity of the enzyme. nitrosylated ferrous iron is particularly stable. hemoglobin is a prominent example of a heme protein that may be modified by no by both direct attack by no and, independently, via attack by s-nitrosothiols, involving no transfer from s to fe. the iron-containing proteins ribonucleotide reductase and aconitase are deactivated by no. no has been demonstrated to activate nf-κb in peripheral blood mononuclear cells, a transcription factor in inos gene expression in response to inflammation. guanylate cyclase although no affects many metalloproteins, it does so by deactivating them. guanylate cyclase is a key component of the famous smooth-muscle relaxing properties of no. it is a heme-containing enzyme that is acted on by no, which binds to the heme. cyclic-gmp activates protein kinase g, which causes reuptake of ca2+ and the opening of calcium-activated potassium channels. the fall in concentration of ca2+ ensures that the myosin light-chain kinase (mlck) can no longer phosphorylate the myosin molecule, thereby stopping the crossbridge cycle and leading to relaxation of the smooth muscle cell. vasodilation and smooth muscles nitric oxide dilates blood vessels, raising blood supply and lowering blood pressure. conversely, it helps protect tissues from damage due to low blood supply. also a neurotransmitter, nitric oxide acts in the nitrergic neurons active on smooth muscle, abundant in the gastrointestinal tract and erectile tissue. sildenafil (viagra) works to inhibit the enzyme phosphodiesterase pde5, which increases the cgmp concentration by inhibiting the conversion to gmp. nitric oxide (no) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. humans with atherosclerosis, diabetes, or hypertension often show impaired no pathways. nitric oxide (no) is a mediator of vasodilation in blood vessels. it is induced by several factors, and once synthesized by enos it results in phosphorylation of several proteins that cause smooth muscle relaxation. the vasodilatory actions of nitric oxide play a key role in renal control of extracellular fluid homeostasis and is essential for the regulation of blood flow and blood pressure. no also plays a role in erection of the penis and clitoris. nitric oxide also acts on cardiac muscle to decrease contractility and heart rate. no contributes to the regulation of cardiac contractility. emerging evidence suggests that coronary artery disease (cad) is related to defects in generation or action of no. effects on plants in plants, nitric oxide can be produced by any of four routes: (i) l-arginine-dependent nitric oxide synthase, (although the existence of animal nos homologs in plants is debated), (ii) plasma membrane-bound nitrate reductase, (iii) mitochondrial electron transport chain, or (iv) non-enzymatic reactions. it is a signaling molecule, acts mainly against oxidative stress and also plays a role in plant pathogen interactions. treating cut flowers and other plants with nitric oxide has been shown to lengthen the time before wilting. in plants, no also regulates some plant-pathogen interaction, promotion of the plant hypersensitive response, symbiosis (for example, with organisms in nitrogen-fixing root nodules), development of lateral and adventitious roots and root hairs, and control of stomatal opening. nitric oxide is known to be produced by cellular organelles, including mitochondria, peroxisomes, and chloroplasts. it plays a role in antioxidant and reactive oxygen species responses. nitric oxide sensing in plants is mediated by the n-end rule of proteolysis and controls abiotic stress responses such as flooding-induced hypoxia, salt and drought stress. nitric oxide interactions have been found within signaling pathways of plant hormones such as auxin, ethylene, abscisic acid and cytokinin. atmospheric nitric oxide can enter the stomates of most vascular species, and can have effects ranging from leaf blemishing, to stunting of growth, to necrosis. effects in insects blood-sucking insects exploit vasodilation induced by no to ensure their blood meal. these insects include cimex lectularius (bed bug) and rhodnius proxlixus (kissing bug). these insects deliver no from its carrier nitrophorin, which is found in their saliva. effects in bacteria while nitric oxide is typically known to halt bacterial growth as part of an immune response, in one case no protects a bacterium. the bacterium deinococcus radiodurans can withstand extreme levels of radioactivity and other stresses. in 2009 it was reported that nitric oxide plays an important role in this bacteria's recovery from radiation exposure: the gas is required for division and proliferation after dna damage has been repaired. a gene that increases nitric oxide production after uv radiation was described, and in the absence of this gene the bacteria were still able to repair dna damage, but would not grow. medical uses nitric oxideclinical datatrade namesinomax, noxivent, genosylahfs/drugs.commonographlicense data eu