Biological functions of nitric oxide

Last updated

Biological functions of nitric oxide are roles that nitric oxide plays within biology.

Contents

Nitric oxide (nitrogen monoxide) is a molecule and chemical compound with chemical formula of N O. In mammals including humans, nitric oxide is a signaling molecule involved in several physiological and pathological processes. [1] 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. [2] 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. [3] 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. [4] 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. [5]

Pathway for nitrosylation of heme-thiolate, steps in cell signalling (porphyrin is depicted as the square). Fe-NO-porph.png
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. [1] 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 [7] [8]

A high salt intake attenuates NO production in patients with essential hypertension, although bioavailability remains unregulated. [9]

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. [10] 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. [11] 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. [12]

The nitrate-nitrite-nitric oxide pathway elevates nitric oxide through the sequential reduction of dietary nitrate derived from plant-based foods. [13] 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. [14] [15] 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. [16] 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. [17] Oral antiseptic mouthwash has been shown to eliminate the blood pressure lowering effects of dietary nitrate due to eradication of nitrate-reducing bacteria. [18]

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. [19] This mechanism may elicit significant changes to the systemic blood circulation in humans and be exploited for therapeutic purposes. [20]

Nasal breathing also produces nitric oxide within the body. [21] [22] [23] [24]

Immune response

A dinitrosyl iron complex (DNIC), the product from the immune responsive attack of NO on Fe-S proteins. DNIC structure.svg
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. [26] 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. [27] [28] [29] 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. [30] Nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania [31] and malaria; [32] [33] [34] the mechanism for this includes DNA damage [35] [36] [37] and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds. [38]

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. [39] However, the role of · N O in inflammation is complex with model studies involving viral infection suggesting that this gaseous mediator can also promote inflammation. [40]

In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance. [41] 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. [42]

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. [43]

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. [44]

The iron-containing proteins ribonucleotide reductase and aconitase are deactivated by NO. [45] NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, a transcription factor in iNOS gene expression in response to inflammation. [46]

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. [47] 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 cross-bridge cycle and leading to relaxation of the smooth muscle cell. [48]

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. [8] Also a neurotransmitter, nitric oxide acts in the nitrergic neurons active on smooth muscle, abundant in the gastrointestinal tract and erectile tissue. [49] 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. [50]

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. [4] 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. [51] NO also plays a role in erection of the penis and clitoris. [52]

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. [53]

Effects on plants

In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase, [54] [55] [56] (although the existence of animal NOS homologs in plants is debated), [57] (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. [58] [59]

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. [60]

Nitric oxide sensing in plants is mediated by the N-end rule of proteolysis [61] [62] and controls abiotic stress responses such as flooding-induced hypoxia, [63] salt and drought stress. [64] [65] [66]

Nitric oxide interactions have been found within signaling pathways of plant hormones such as auxin, [67] ethylene, [63] [68] [69] Abscisic acid [61] and cytokinin. [70]

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. [71]

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. [6]

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. [72]

Medical uses

Nitric oxide
Nitric-oxide-3D-vdW.png
Clinical data
Trade names Inomax, Noxivent, Genosyl
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		Inhalation
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
  • Nitric oxide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula NO
Molar mass 30.006 g·mol−1
3D model (JSmol)
  • [N]=O
  • InChI=1S/NO/c1-2
  • Key:MWUXSHHQAYIFBG-UHFFFAOYSA-N

In the European Union, nitric oxide in conjunction with ventilatory support and other appropriate active substances, is indicated: [74]

In the United States, it is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. [75]

The most common side effects include thrombocytopenia (low blood platelet counts), hypokalaemia (low blood potassium levels), hypotension (low blood pressure), atelectasis (collapse of the whole, or part of a, lung), and hyperbilirubinaemia (high blood levels of bilirubin). [74]

Nitric oxide was approved for medical use in the United States in December 1999 and for medical use in the European Union in 2001. [76] [74] [75]

Nitric oxide can be delivered as a pulse in the beginning of each breath to horses during anaesthesia. This is called PiNO (pulsed inhaled nitric oxide) and results in better matching of ventilation and perfusion and thereby improves the arterial oxygenation. [77] [78]

Associated problems

There are some associated complaints with utilization of nitric oxide in neonatal patients. Some of them include dose errors associated with the delivery system, headaches associated with environmental exposure of nitric oxide in hospital staff, hypotension associated with acute withdrawal of the drug, hypoxemia associated with acute withdrawal of the drug, and pulmonary edema in patients with CREST syndrome.[ citation needed ]

Contraindications

Inhaled nitric oxide is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood. This is as the nitric oxide decreases the pulmonary circulation's resistance by dilating pulmonary blood vessels. The increased pulmonary return increases pressure in the left atrium, causing closure of the foramen ovale and reducing the blood flow through the ductus arteriosus. Closing these shunts can kill neonates with heart malformations that rely on the right-to-left shunting of blood.[ citation needed ]

Dosage and strength

In the United States, nitric oxide is a gas available in concentrations of only 100 ppm and 800 ppm. Overdosage with inhaled nitric oxide will be seen by elevations in methemoglobin and pulmonary toxicities associated with inspired ·NO. Elevated NO may cause acute lung injury.[ citation needed ]

Fatty liver disease

Nitric oxide production is associated with nonalcoholic fatty liver disease (NAFLD) and is essential for hepatic lipid metabolism under starvation. [79]

Lung infection

Nitric oxide is a potential therapeutic intervention in acute and chronic lung infections. [80] [81]

Mechanism of action

Nitric oxide is a cell signaling molecule produced by many cells of the body, and growing evidence suggests that the biological actions of the endocannabinoid system (ECS) may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide. [82] It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic-guanosine 3',5'-monophosphate (cGMP). The elevation of intracellular cGMP results in relaxation by the activation of cGMP-dependent protein kinase, which phosphorylates target proteins such as the myosin phosphatase-targeting subunit (MYPT) and the IP3 receptor-associated cGMP kinase substrate (IRAG). In addition, cGMP has been proposed to also cause smooth muscle relaxation indirectly by increasing levels of cAMP. [83]

When inhaled, nitric oxide dilates the pulmonary vasculature and, because of efficient scavenging by hemoglobin, has minimal effect on the vasculature of the entire body. [84]

Inhaled nitric oxide appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better-ventilated areas of the lung, moving pulmonary blood flow away from lung segments with low ventilation/perfusion (V/Q) ratios toward segments with normal or better ratios. [85]

Neonatal use

Nitric oxide/oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat primary pulmonary hypertension in neonatal patients [86] [87] and post-meconium aspiration related to birth defects. These are often a last-resort gas mixture before the use of extracorporeal membrane oxygenation (ECMO). Nitric oxide therapy has the potential to significantly increase the quality of life and, in some cases, save the lives of infants at risk for pulmonary vascular disease. [88]

Pathology

People with diabetes usually have lower levels of nitric oxide than patients without diabetes. [89] Diminished supply of nitric oxide can lead to vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage can lead to decreased blood flow to the extremities, causing the diabetic patient to be more likely to develop neuropathy and non-healing ulcers, and to be at a greater risk for lower limb amputation.

Pediatric and adult use

The primary use is in the form of nitroglycerin, either pill or liquid spray forms, which, as a prodrug, is denitrated and releases the active metabolite nitric oxide (NO). As with all supplements of nitric oxide, the response is short-lived because, as a normally produced internal physiologic control mechanism, increased concentrations lead to increased rates of clearance, which is the reason that the effectiveness of sustained use of nitroglycerin for vasodilation fades to none after hours to days. In the United States, ongoing direct use of nitric oxide use is only approved for neonates. In the adult ICU setting, inhaled ·NO can improve hypoxemia in acute lung injury, acute respiratory distress syndrome, and severe pulmonary hypertension, although the effects are short-lived and there are no studies demonstrating improved clinical outcomes. It is used on an individualized basis in ICUs as an adjunct to other definitive therapies for reversible causes of hypoxemic respiratory distress. [90]

Pharmacokinetics

Nitric oxide is absorbed systemically after inhalation. Most of it moves across the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated.

Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.[ citation needed ]

Pharmacology

Nitric oxide is considered an anti anginal drug: It causes vasodilation, which can help with ischemic pain, known as angina, by decreasing the cardiac workload. By dilating (expanding) the arteries, nitric oxide drugs lower arterial pressure and left ventricular filling pressure. [91] Nitric oxide can contribute to reperfusion injury when an excessive amount produced during reperfusion (following a period of ischemia) reacts with superoxide to produce the damaging oxidant peroxynitrite. In contrast, inhaled nitric oxide has been shown to help survival and recovery from paraquat poisoning, which produces lung tissue-damaging superoxide and hinders NOS metabolism.

This vasodilation does not decrease the volume of blood the heart pumps, but rather it decreases the force the heart muscle must exert to pump the same volume of blood. Nitroglycerin pills, taken sublingually (under the tongue), are used to prevent or treat acute chest pain. The nitroglycerin reacts with a sulfhydryl group (–SH) to produce nitric oxide, which eases the pain by causing vasodilation. There is a potential role for the use of nitric oxide in alleviating bladder contractile dysfunctions, [92] [93] and recent evidence suggests that nitrates may be beneficial for treatment of angina due to reduced myocardial oxygen consumption both by decreasing preload and afterload and by some direct vasodilation of coronary vessels. [91]

Pulmonary embolism

Nitric oxide is also administered as salvage therapy in patients with acute right ventricular failure secondary to pulmonary embolism. [94]

Research

COVID-19

As of April 2020, studies and trials are underway that examine the possible benefits of nitric oxide in the treatment of COVID-19. [95] [96] [97] [98] This research is based on the fact that nitric oxide was investigated as an experimental therapy for SARS. [99] Brian Strickland, MD, a fellow in Wilderness Medicine at Massachusetts General Hospital who studies "acute respiratory distress" in high altitudes, is applying this research towards COVID-19. [100] [101] He is involved in clinical trials which apply the use of inhaled nitric oxide as a treatment for COVID-19. [102] This approach was inspired by the work of associate professor of emergency medicine at the Harvard Medical School N. Stuart Harris, who has been studying the effects of altitude sickness on mountain climbers, such as those who climb Mount Everest. Harris noticed that the consequences of high level altitude sickness on the human body mirrored COVID-19's dysfunctional impact on the lungs. His focus on nitric oxide comes from its role in being able to breathe in high altitudes. [100] [103] According to WCVB-TV, similar trials are being conducted at Tufts Medical Center. [104] Other studies speculate that replacing mouth breathing (which decimates NO) with nasal breathing (which increases NO) [21] [22] [23] [24] is a "lifestyle change" that "may also help to reduce SARS-CoV-2 viral load and symptoms of COVID‑19 pneumonia by promoting more efficient antiviral defense mechanisms in the respiratory tract." [105]

Cardiac protection

It is found, that the naturally occurring cannabinoid compound delta-9-tetrahydrocannabinol (THC: C21H30O2), appearing in Cannabis , increase NO production in neonatal cardiac cells through the induction of the inducible nitric oxide synthase (iNOS) activity in a CB2 receptor dependent manner, while increasing endothelial nitric oxide synthase (eNOS) expression in diabetic hearts subject to ischaemia/reperfusion (I/R), thereby protecting cardiac cells from hypoxic damage, probably by pre-training the cardiomyocytes to hypoxic conditions, as an NOS inhibitor was able to block the THC-induced cardioprotective action. [106] The activation of mainly CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect of cannabinoids. [107]

Related Research Articles

<span class="mw-page-title-main">Nitrate</span> Polyatomic ion (NO₃, charge –1) found in explosives and fertilisers

Nitrate is a polyatomic ion with the chemical formula NO−
3. Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insoluble nitrate is bismuth oxynitrate.

<span class="mw-page-title-main">Sodium nitrite</span> Chemical compound

Sodium nitrite is an inorganic compound with the chemical formula NaNO2. It is a white to slightly yellowish crystalline powder that is very soluble in water and is hygroscopic. From an industrial perspective, it is the most important nitrite salt. It is a precursor to a variety of organic compounds, such as pharmaceuticals, dyes, and pesticides, but it is probably best known as a food additive used in processed meats and (in some countries) in fish products.

<span class="mw-page-title-main">Pulmonary hypertension</span> Increased blood pressure in lung arteries

Pulmonary hypertension is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual. According to the definition at the 6th World Symposium of Pulmonary Hypertension in 2018, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmHg at rest, revised down from a purely arbitrary 25mmHg, and pulmonary vascular resistance (PVR) greater than 3 Wood units.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

<span class="mw-page-title-main">Tetrahydrobiopterin</span> Chemical compound

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

<span class="mw-page-title-main">Spermidine</span> Chemical compound

Spermidine is a polyamine compound found in ribosomes and living tissues and having various metabolic functions within organisms. It was originally isolated from semen.

<span class="mw-page-title-main">Nitroglycerin (medication)</span> Medication

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure (hypertension), anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.

Gasotransmitters is a class of neurotransmitters. The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria. Currently, only nitric oxide, carbon monoxide, and hydrogen sulfide are accepted as gasotransmitters. According to in vitro models, gasotransmitters, like other gaseous signaling molecules, may bind to gasoreceptors and trigger signaling in the cells.

<span class="mw-page-title-main">Nicorandil</span> Chemical compound

Nicorandil is a vasodilator drug used to treat angina.

Portopulmonary hypertension (PPH) is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients with cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition. Today, PPH is comorbid in 4-6% of those referred for a liver transplant.

<span class="mw-page-title-main">Endothelial NOS</span> Protein and coding gene in humans

Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes. The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases. eNOS is primarily responsible for the generation of NO in the vascular endothelium, a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall. NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation. Therefore, a functional eNOS is essential for a healthy cardiovascular system.

<span class="mw-page-title-main">7-Nitroindazole</span> Chemical compound

7-Nitroindazole, or 7-NI, is a heterocyclic small molecule containing an indazole ring that has been nitrated at the 7 position. Nitroindazole acts as a selective inhibitor for neuronal nitric oxide synthase, a hemoprotein enzyme that, in neuronal tissue, converts arginine to citrulline and nitric oxide (NO). Nitric oxide can diffuse through the plasma membrane into neighbouring cells, allowing cell signalling, so nitroindazole indirectly inhibits this signalling process. Other inhibitors exist such as 3-bromo-7-nitroindazole, which is more potent but less specific, or NPA (N-propyl-L-arginine), which acts on a different site.

<span class="mw-page-title-main">Exhaled nitric oxide</span> Breath test for respiratory inflammation

In medicine, exhaled nitric oxide (eNO) can be measured in a breath test for asthma and other respiratory conditions characterized by airway inflammation. Nitric oxide (NO) is a gaseous molecule produced by certain cell types in an inflammatory response. The fraction of exhaled NO (FENO) is a promising biomarker for the diagnosis, follow-up and as a guide to therapy in adults and children with asthma. The breath test has recently become available in many well-equipped hospitals in developed countries, although its exact role remains unclear.

Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension. It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.

<span class="mw-page-title-main">Nitrovasodilator</span> Drug that causes vasodilation by releasing nitric oxide

A nitrovasodilator is a pharmaceutical agent that causes vasodilation by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris.

<span class="mw-page-title-main">Riociguat</span> Chemical compound

Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylate cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of the class of sGC stimulators. The drug has a half-life of 12 hours and will decrease dyspnea associated with pulmonary arterial hypertension.

<i>S</i>-Nitrosoglutathione Chemical compound

S-Nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol (SNO) that plays a critical role in nitric oxide (NO) signaling and is a source of bioavailable NO. NO coexists in cells with SNOs that serve as endogenous NO carriers and donors. SNOs spontaneously release NO at different rates and can be powerful terminators of free radical chain propagation reactions, by reacting directly with ROO• radicals, yielding nitro derivatives as end products. NO is generated intracellularly by the nitric oxide synthase (NOS) family of enzymes: nNOS, eNOS and iNOS while the in vivo source of many of the SNOs is unknown. In oxygenated buffers, however, formation of SNOs is due to oxidation of NO to dinitrogen trioxide (N2O3). Some evidence suggests that both exogenous NO and endogenously derived NO from nitric oxide synthases can react with glutathione to form GSNO.

<span class="mw-page-title-main">Sodium nitroprusside</span> Medication for lowering blood pressure

Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and during surgery to decrease bleeding. It is used by continuous injection into a vein. Onset is nearly immediate and effects last for up to ten minutes.

Gaseous signaling molecules are gaseous molecules that are either synthesized internally (endogenously) in the organism, tissue or cell or are received by the organism, tissue or cell from outside and that are used to transmit chemical signals which induce certain physiological or biochemical changes in the organism, tissue or cell. The term is applied to, for example, oxygen, carbon dioxide, sulfur dioxide, nitrous oxide, hydrogen cyanide, ammonia, methane, hydrogen, ethylene, etc.

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).

References

  1. ↑ Culotta E, Koshland DE (December 1992). "NO news is good news". Science. 258 (5090): 1862–1865. Bibcode:1992Sci...258.1862C. doi:10.1126/science.1361684. PMID   1361684.
  2. ↑ Ignarro LJ (November 1990). "Nitric oxide. A novel signal transduction mechanism for transcellular communication". Hypertension. 16 (5). Dallas, Texas: 477–83. doi: 10.1161/01.hyp.16.5.477 . PMID   1977698.
  3. 1 2 Weller R (January 2013). "Could the sun be good for your heart?". TedxGlasgow. Archived from the original on 2014-02-16.
  4. ↑ Davies SA, Stewart EJ, Huesmann GR, Skaer NJ, Maddrell SH, Tublitz NJ, Dow JA (August 1997). "Neuropeptide stimulation of the nitric oxide signaling pathway in Drosophila melanogaster Malpighian tubules". The American Journal of Physiology. 273 (2 Pt 2): R823–R827. doi:10.1152/ajpregu.1997.273.2.R823. PMID   9277574.
  5. 1 2 Walker FA (January 2005). "Nitric oxide interaction with insect nitrophorins and thoughts on the electron configuration of the {FeNO}6 complex". Journal of Inorganic Biochemistry. 99 (1): 216–236. doi:10.1016/j.jinorgbio.2004.10.009. PMID   15598503.
  6. ↑ van Faassen E, Vanin A, eds. (2007). Radicals for life: The various forms of nitric oxide. Amsterdam: Elsevier. ISBN   978-0-444-52236-8.
  7. 1 2 van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, et al. (September 2009). "Nitrite as regulator of hypoxic signaling in mammalian physiology". Medicinal Research Reviews. 29 (5): 683–741. doi:10.1002/med.20151. PMC   2725214 . PMID   19219851.
  8. ↑ Osanai T, Fujiwara N, Saitoh M, Sasaki S, Tomita H, Nakamura M, et al. (2002). "Relationship between salt intake, nitric oxide and asymmetric dimethylarginine and its relevance to patients with end-stage renal disease". Blood Purification. 20 (5): 466–468. doi:10.1159/000063555. PMID   12207094. S2CID   46833231.
  9. ↑ Liu AH, Bondonno CP, Croft KD, Puddey IB, Woodman RJ, Rich L, et al. (November 2013). "Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers". Nitric Oxide. 35: 123–130. doi:10.1016/j.niox.2013.10.001. PMID   24120618.
  10. ↑ Lundberg JO, Weitzberg E, Gladwin MT (February 2008). "The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics". Nature Reviews. Drug Discovery. 7 (2): 156–167. doi:10.1038/nrd2466. PMID   18167491. S2CID   5141850.
  11. ↑ Green SJ (June 1995). "Nitric oxide in mucosal immunity". Nature Medicine. 1 (6): 515–517. doi:10.1038/nm0695-515. PMID   7585111. S2CID   36184793.
  12. ↑ "Plant-based Diets | Plant-based Foods | Beetroot Juice | Nitric Oxide Vegetables". Berkeley Test. Archived from the original on 2013-10-04. Retrieved 2013-10-04.
  13. ↑ Ghosh SM, Kapil V, Fuentes-Calvo I, Bubb KJ, Pearl V, Milsom AB, et al. (May 2013). "Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential". Hypertension. 61 (5): 1091–1102. doi: 10.1161/HYPERTENSIONAHA.111.00933 . PMID   23589565.
  14. ↑ Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, et al. (March 2008). "Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite". Hypertension. 51 (3): 784–790. doi:10.1161/HYPERTENSIONAHA.107.103523. PMC   2839282 . PMID   18250365.
  15. ↑ Hezel MP, Weitzberg E (January 2015). "The oral microbiome and nitric oxide homoeostasis". Oral Diseases. 21 (1): 7–16. doi: 10.1111/odi.12157 . PMID   23837897.
  16. ↑ Green SJ (2013-07-25). "Turning DASH Strategy into Reality for Improved Cardio Wellness Outcomes: Part II". Real World Health Care. Retrieved 2013-10-04.
  17. ↑ Bryan NS, Tribble G, Angelov N (2017). "Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure". Current Hypertension Reports . 19 (4): 33. doi:10.1007/s11906-017-0725-2. PMID   28353075.
  18. ↑ Suschek CV, Opländer C, van Faassen EE (February 2010). "Non-enzymatic NO production in human skin: effect of UVA on cutaneous NO stores". Nitric Oxide. 22 (2): 120–135. doi:10.1016/j.niox.2009.10.006. PMID   19879370.
  19. ↑ Opländer C, Römer A, Paunel-Görgülü A, Fritsch T, van Faassen EE, Mürtz M, et al. (June 2012). "Dermal application of nitric oxide in vivo: kinetics, biological responses, and therapeutic potential in humans". Clinical Pharmacology and Therapeutics. 91 (6): 1074–1082. doi:10.1038/clpt.2011.366. PMID   22549282. S2CID   32190689.
  20. 1 2 Glazier E (2019-11-04). "'Nose breathing has more benefits than mouth breathing". The Times and Democrat . Retrieved 2020-07-09.
  21. 1 2 Dahl M (2011-01-11). "'Mouth-breathing' gross, harmful to your health". NBC News. Retrieved 2020-06-28.
  22. 1 2 Berman J (2019-01-29). "Could nasal breathing improve athletic performance?". The Washington Post . Retrieved 2020-05-31.
  23. 1 2 Vinopal L (2019-07-19). "Undiagnosed Mouth Breathing Creates Unhealthy Kids". Fatherly . Retrieved 2020-05-31.
  24. ↑ Fitzpatrick J, Kim E (August 2015). "Synthetic modeling chemistry of iron-sulfur clusters in nitric oxide signaling". Accounts of Chemical Research. 48 (8): 2453–2461. doi:10.1021/acs.accounts.5b00246. PMID   26197209.
  25. ↑ Green SJ, Mellouk S, Hoffman SL, Meltzer MS, Nacy CA (August 1990). "Cellular mechanisms of nonspecific immunity to intracellular infection: cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes". Immunology Letters. 25 (1–3): 15–19. doi:10.1016/0165-2478(90)90083-3. PMID   2126524.
  26. ↑ Gorczynski RM, Stanley J (1999). Clinical Immunology. Austin, TX: Landes Bioscience. ISBN   978-1-57059-625-4. OCLC   52342536.
  27. ↑ Green SJ, Nacy CA, Schreiber RD, Granger DL, Crawford RM, Meltzer MS, Fortier AH (February 1993). "Neutralization of gamma interferon and tumor necrosis factor alpha blocks in vivo synthesis of nitrogen oxides from L-arginine and protection against Francisella tularensis infection in Mycobacterium bovis BCG-treated mice". Infection and Immunity. 61 (2): 689–698. doi:10.1128/IAI.61.2.689-698.1993. PMC   302781 . PMID   8423095.
  28. ↑ Kamijo R, Gerecitano J, Shapiro D, Green SJ, Aguet M, Le J, Vilcek J (1995). "Generation of nitric oxide and clearance of interferon-gamma after BCG infection are impaired in mice that lack the interferon-gamma receptor". Journal of Inflammation. 46 (1): 23–31. PMID   8832969.
  29. ↑ Green SJ, Scheller LF, Marletta MA, Seguin MC, Klotz FW, Slayter M, et al. (December 1994). "Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens". Immunology Letters. 43 (1–2): 87–94. doi:10.1016/0165-2478(94)00158-8. hdl: 2027.42/31140 . PMID   7537721.
  30. ↑ Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA (December 1990). "Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha". Journal of Immunology. 145 (12): 4290–4297. doi:10.4049/jimmunol.145.12.4290. PMID   2124240. S2CID   21034574.
  31. ↑ Seguin MC, Klotz FW, Schneider I, Weir JP, Goodbary M, Slayter M, et al. (July 1994). "Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells". The Journal of Experimental Medicine. 180 (1): 353–358. doi:10.1084/jem.180.1.353. PMC   2191552 . PMID   7516412.
  32. ↑ Mellouk S, Green SJ, Nacy CA, Hoffman SL (June 1991). "IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism". Journal of Immunology. 146 (11): 3971–3976. doi: 10.4049/jimmunol.146.11.3971 . PMID   1903415. S2CID   45487458.
  33. ↑ Klotz FW, Scheller LF, Seguin MC, Kumar N, Marletta MA, Green SJ, Azad AF (April 1995). "Co-localization of inducible-nitric oxide synthase and Plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites". Journal of Immunology. 154 (7): 3391–3395. doi: 10.4049/jimmunol.154.7.3391 . PMID   7534796. S2CID   12612236.
  34. ↑ Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, et al. (November 1991). "DNA deaminating ability and genotoxicity of nitric oxide and its progenitors". Science. 254 (5034): 1001–1003. Bibcode:1991Sci...254.1001W. doi:10.1126/science.1948068. PMID   1948068.
  35. ↑ Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR (April 1992). "DNA damage and mutation in human cells exposed to nitric oxide in vitro". Proceedings of the National Academy of Sciences of the United States of America. 89 (7): 3030–3034. Bibcode:1992PNAS...89.3030N. doi: 10.1073/pnas.89.7.3030 . PMC   48797 . PMID   1557408. Free text.
  36. ↑ Li CQ, Pang B, Kiziltepe T, Trudel LJ, Engelward BP, Dedon PC, Wogan GN (March 2006). "Threshold effects of nitric oxide-induced toxicity and cellular responses in wild-type and p53-null human lymphoblastoid cells". Chemical Research in Toxicology. 19 (3): 399–406. doi:10.1021/tx050283e. PMC   2570754 . PMID   16544944. free text
  37. ↑ Hibbs JB, Taintor RR, Vavrin Z, Rachlin EM (November 1988). "Nitric oxide: a cytotoxic activated macrophage effector molecule". Biochemical and Biophysical Research Communications. 157 (1): 87–94. doi:10.1016/S0006-291X(88)80015-9. PMID   3196352.
  38. ↑ Wallace JL, Ianaro A, Flannigan KL, Cirino G (May 2015). "Gaseous mediators in resolution of inflammation". Seminars in Immunology. 27 (3): 227–233. doi:10.1016/j.smim.2015.05.004. PMID   26095908.
  39. ↑ Uehara EU, Shida BD, de Brito CA (November 2015). "Role of nitric oxide in immune responses against viruses: beyond microbicidal activity". Inflammation Research. 64 (11): 845–852. doi:10.1007/s00011-015-0857-2. PMID   26208702. S2CID   14587150.
  40. ↑ Janeway, C. A.; et al. (2005). Immunobiology: the immune system in health and disease (6th ed.). New York: Garland Science. ISBN   978-0-8153-4101-7.
  41. ↑ Jacobs L, Nawrot TS, de Geus B, Meeusen R, Degraeuwe B, Bernard A, et al. (October 2010). "Subclinical responses in healthy cyclists briefly exposed to traffic-related air pollution: an intervention study". Environmental Health. 9 (64): 64. Bibcode:2010EnvHe...9...64J. doi: 10.1186/1476-069X-9-64 . PMC   2984475 . PMID   20973949.
  42. ↑ van Faassen E, Vanin A (2007). Radicals for life: The various forms of nitric oxide. Amsterdam: Elsevier. ISBN   978-0-444-52236-8.
  43. ↑ van Faassen E, Vanin A (2004). "Nitric Oxide". Encyclopedia of Analytical Science (2nd ed.). Elsevier. ISBN   978-0-12-764100-3.
  44. ↑ Shami PJ, Moore JO, Gockerman JP, Hathorn JW, Misukonis MA, Weinberg JB (August 1995). "Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells". Leukemia Research. 19 (8): 527–533. doi:10.1016/0145-2126(95)00013-E. PMID   7658698.
  45. ↑ Kaibori M, Sakitani K, Oda M, Kamiyama Y, Masu Y, Nishizawa M, et al. (June 1999). "Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-kappaB activation in rat hepatocytes". Journal of Hepatology. 30 (6): 1138–1145. doi:10.1016/S0168-8278(99)80270-0. PMID   10406194.
  46. ↑ Derbyshire ER, Marletta MA (2009). "Biochemistry of Soluble Guanylate Cyclase". CGMP: Generators, Effectors and Therapeutic Implications. Handbook of Experimental Pharmacology. Vol. 191. pp. 17–31. doi:10.1007/978-3-540-68964-5_2. ISBN   978-3-540-68960-7. PMID   19089323. S2CID   25597341.
  47. ↑ Rhoades RA, Tanner GA (2003). Medical physiology (2nd ed.).
  48. ↑ Toda N, Ayajiki K, Okamura T (May 2005). "Nitric oxide and penile erectile function". Pharmacology & Therapeutics. 106 (2): 233–266. doi:10.1016/j.pharmthera.2004.11.011. PMID   15866322.
  49. ↑ Dessy C, Feron O (2004). "Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature". Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents. 3 (3): 207–216. doi:10.2174/1568014043355348.
  50. ↑ Yoon Y, Song J, Hong SH, Kim JQ (October 2000). "Plasma nitric oxide concentrations and nitric oxide synthase gene polymorphisms in coronary artery disease". Clinical Chemistry. 46 (10): 1626–1630. doi: 10.1093/clinchem/46.10.1626 . PMID   11017941.
  51. ↑ Gragasin FS, Michelakis ED, Hogan A, Moudgil R, Hashimoto K, Wu X, et al. (September 2004). "The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels". FASEB Journal. 18 (12): 1382–1391. doi: 10.1096/fj.04-1978com . PMID   15333581. S2CID   45447939.
  52. ↑ Thakur NK, Hayashi T, Sumi D, Kano H, Matsui-Hirai H, Tsunekawa T, Iguchi A (February 2002). "Anti-atherosclerotic effect of beta-blocker with nitric oxide-releasing action on the severe atherosclerosis". Journal of Cardiovascular Pharmacology. 39 (2): 298–309. doi: 10.1097/00005344-200202000-00017 . PMID   11791016. S2CID   24712179.
  53. ↑ Corpas FJ, Barroso JB, Carreras A, Quirós M, León AM, Romero-Puertas MC, et al. (September 2004). "Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea plants". Plant Physiology. 136 (1): 2722–2733. doi:10.1104/pp.104.042812. PMC   523336 . PMID   15347796.
  54. ↑ Corpas FJ, Barroso JB, Carreras A, Valderrama R, Palma JM, León AM, et al. (July 2006). "Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development". Planta. 224 (2): 246–254. Bibcode:2006Plant.224..246C. doi:10.1007/s00425-005-0205-9. PMID   16397797. S2CID   23329722.
  55. ↑ Valderrama R, Corpas FJ, Carreras A, Fernández-Ocaña A, Chaki M, Luque F, et al. (February 2007). "Nitrosative stress in plants". FEBS Letters. 581 (3): 453–461. doi: 10.1016/j.febslet.2007.01.006 . PMID   17240373. S2CID   34725559.
  56. ↑ Corpas FJ, Barroso JB, Del Río LA (2004). "Enzymatic sources of nitric oxide in plant cells – beyond one protein–one function". New Phytologist. 162 (2): 246–7. doi: 10.1111/j.1469-8137.2004.01058.x .
  57. ↑ Tuffs A (July 1999). "Max-Planck Society investigates misconduct". BMJ. 319 (7205): 274. doi:10.1136/bmj.319.7205.274a. PMC   1126920 . PMID   10426722.
  58. ↑ Mur LA, Mandon J, Persijn S, Cristescu SM, Moshkov IE, Novikova GV, et al. (2013). "Nitric oxide in plants: an assessment of the current state of knowledge". AoB Plants. 5: pls052. doi:10.1093/aobpla/pls052. PMC   3560241 . PMID   23372921.
  59. ↑ Verma K, Mehta SK, Shekhawat GS (April 2013). "Nitric oxide (NO) counteracts cadmium induced cytotoxic processes mediated by reactive oxygen species (ROS) in Brassica juncea: cross-talk between ROS, NO and antioxidant responses". Biometals. 26 (2): 255–269. doi:10.1007/s10534-013-9608-4. PMID   23322177. S2CID   254285519.
  60. 1 2 Gibbs DJ, Md Isa N, Movahedi M, Lozano-Juste J, Mendiondo GM, Berckhan S, et al. (February 2014). "Nitric oxide sensing in plants is mediated by proteolytic control of group VII ERF transcription factors". Molecular Cell. 53 (3): 369–379. doi: 10.1016/j.molcel.2013.12.020 . PMC   3969242 . PMID   24462115.
  61. ↑ León J, Costa-Broseta Á, Castillo MC (May 2020). "RAP2.3 negatively regulates nitric oxide biosynthesis and related responses through a rheostat-like mechanism in Arabidopsis". Journal of Experimental Botany. 71 (10): 3157–3171. doi: 10.1093/jxb/eraa069 . PMC   7260729 . PMID   32052059.
  62. 1 2 Hartman S, Liu Z, van Veen H, Vicente J, Reinen E, Martopawiro S, et al. (September 2019). "Ethylene-mediated nitric oxide depletion pre-adapts plants to hypoxia stress". Nature Communications. 10 (1): 4020. Bibcode:2019NatCo..10.4020H. doi: 10.1038/s41467-019-12045-4 . PMC   6728379 . PMID   31488841.
  63. ↑ Vicente J, Mendiondo GM, Movahedi M, Peirats-Llobet M, Juan YT, Shen YY, et al. (October 2017). "The Cys-Arg/N-End Rule Pathway Is a General Sensor of Abiotic Stress in Flowering Plants". Current Biology. 27 (20): 3183–3190.e4. doi: 10.1016/j.cub.2017.09.006 . PMC   5668231 . PMID   29033328.
  64. ↑ Castillo MC, Costa-Broseta Á, Gayubas B, León J (December 2021). "NIN-like protein7 and PROTEOLYSIS6 functional interaction enhances tolerance to sucrose, ABA, and submergence". Plant Physiology. 187 (4): 2731–2748. doi:10.1093/plphys/kiab382. PMC   8644111 . PMID   34618055.
  65. ↑ Hartman S (December 2021). "NIN-like Protein7 is controlled by oxygen and nitric oxide and contributes to stress tolerance through PROTEOLYSIS6". Plant Physiology. 187 (4): 2346–2347. doi:10.1093/plphys/kiab415. PMC   8644194 . PMID   34890464.
  66. ↑ Terrile MC, París R, Calderón-Villalobos LI, Iglesias MJ, Lamattina L, Estelle M, Casalongué CA (May 2012). "Nitric oxide influences auxin signaling through S-nitrosylation of the Arabidopsis TRANSPORT INHIBITOR RESPONSE 1 auxin receptor". The Plant Journal. 70 (3): 492–500. doi:10.1111/j.1365-313X.2011.04885.x. PMC   3324642 . PMID   22171938.
  67. ↑ Melo NK, Bianchetti RE, Lira BS, Oliveira PM, Zuccarelli R, Dias DL, et al. (April 2016). "Nitric Oxide, Ethylene, and Auxin Cross Talk Mediates Greening and Plastid Development in Deetiolating Tomato Seedlings". Plant Physiology. 170 (4): 2278–2294. doi: 10.1104/pp.16.00023 . PMC   4825133 . PMID   26829981.
  68. ↑ Zhang L, Li G, Wang M, Di D, Sun L, Kronzucker HJ, Shi W (July 2018). "Excess iron stress reduces root tip zone growth through nitric oxide-mediated repression of potassium homeostasis in Arabidopsis". The New Phytologist. 219 (1): 259–274. doi: 10.1111/nph.15157 . hdl: 11343/283842 . PMID   29658100.
  69. ↑ Liu WZ, Kong DD, Gu XX, Gao HB, Wang JZ, Xia M, et al. (January 2013). "Cytokinins can act as suppressors of nitric oxide in Arabidopsis". Proceedings of the National Academy of Sciences of the United States of America. 110 (4): 1548–1553. Bibcode:2013PNAS..110.1548L. doi: 10.1073/pnas.1213235110 . PMC   3557067 . PMID   23319631.
  70. ↑ Hogan CM (2010). "Abiotic factor". In Monosson E, Cleveland C (eds.). Encyclopedia of Earth . Washington DC: National Council for Science and the Environment. Archived from the original on June 8, 2013.
  71. ↑ Patel BA, Moreau M, Widom J, Chen H, Yin L, Hua Y, Crane BR (October 2009). "Endogenous nitric oxide regulates the recovery of the radiation-resistant bacterium Deinococcus radiodurans from exposure to UV light". Proceedings of the National Academy of Sciences of the United States of America. 106 (43): 18183–18188. Bibcode:2009PNAS..10618183P. doi: 10.1073/pnas.0907262106 . PMC   2775278 . PMID   19841256.
  72. ↑ "Nitric oxide Use During Pregnancy". Drugs.com. 21 November 2019. Retrieved 29 May 2020.
  73. 1 2 3 4 5 "Inomax EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  74. 1 2 "Inomax- nitric oxide gas". DailyMed. U.S. National Library of Medicine. 25 February 2019. Retrieved 29 May 2020.
  75. ↑ "Drug Approval Package: Inomax (Nitric Oxide) NDA# 20-845". U.S. Food and Drug Administration (FDA). 31 March 2001. Retrieved 29 May 2020.
  76. ↑ Wiklund M, Granswed I, Nyman G (September 2017). "Pulsed inhaled nitric oxide improves arterial oxygenation in colic horses undergoing abdominal surgery". Veterinary Anaesthesia and Analgesia. 44 (5): 1139–1148. doi:10.1016/j.vaa.2016.11.015. PMID   29051000.
  77. ↑ Wiklund M, Kellgren M, Wulcan S, Grubb T, Nyman G (January 2020). "Effects of pulsed inhaled nitric oxide on arterial oxygenation during mechanical ventilation in anaesthetised horses undergoing elective arthroscopy or emergency colic surgery". Equine Veterinary Journal. 52 (1): 76–82. doi:10.1111/evj.13129. PMID   31009091. S2CID   128175609.
  78. ↑ Gu Q, Yang X, Lin L, Li S, Li Q, Zhong S, et al. (December 2014). "Genetic ablation of solute carrier family 7a3a leads to hepatic steatosis in zebrafish during fasting". Hepatology. 60 (6): 1929–1941. doi: 10.1002/hep.27356 . PMID   25130427. S2CID   205894350.
  79. ↑ Fang FC (October 2004). "Antimicrobial reactive oxygen and nitrogen species: concepts and controversies". Nature Reviews. Microbiology. 2 (10): 820–832. doi:10.1038/nrmicro1004. PMID   15378046. S2CID   11063073.
  80. ↑ Goldfarb RD, Cinel I (January 2007). "Inhaled nitric oxide therapy for sepsis: more than just lung". Critical Care Medicine. 35 (1): 290–292. doi:10.1097/01.CCM.0000251290.41866.2B. PMID   17197767.
  81. ↑ Lipina C, Hundal HS (April 2017). "The endocannabinoid system: 'NO' longer anonymous in the control of nitrergic signalling?". Journal of Molecular Cell Biology. 9 (2): 91–103. doi:10.1093/jmcb/mjx008. PMC   5439392 . PMID   28130308.
  82. ↑ Krawutschke C, Koesling D, Russwurm M (September 2015). "Cyclic GMP in Vascular Relaxation: Export Is of Similar Importance as Degradation". Arteriosclerosis, Thrombosis, and Vascular Biology. 35 (9): 2011–2019. doi: 10.1161/ATVBAHA.115.306133 . PMID   26205960.
  83. ↑ Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. (July 2006). "Early inhaled nitric oxide therapy in premature newborns with respiratory failure". The New England Journal of Medicine. 355 (4): 354–364. CiteSeerX   10.1.1.319.6088 . doi:10.1056/NEJMoa060442. PMID   16870914.
  84. ↑ Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. (July 2006). "Inhaled nitric oxide in preterm infants undergoing mechanical ventilation". The New England Journal of Medicine. 355 (4): 343–353. doi: 10.1056/NEJMoa061088 . PMID   16870913.
  85. ↑ Barrington KJ, Finer N, Pennaforte T, Altit G (January 2017). "Nitric oxide for respiratory failure in infants born at or near term". The Cochrane Database of Systematic Reviews. 1 (1): CD000399. doi:10.1002/14651858.CD000399.pub3. PMC   6464941 . PMID   28056166.
  86. ↑ Chotigeat U, Khorana M, Kanjanapattanakul W (February 2007). "Inhaled nitric oxide in newborns with severe hypoxic respiratory failure". Journal of the Medical Association of Thailand = Chotmaihet Thangphaet. 90 (2): 266–271. PMID   17375630.
  87. ↑ Hayward CS, Kelly RP, Macdonald PS (August 1999). "Inhaled nitric oxide in cardiology practice". Cardiovascular Research. 43 (3): 628–638. doi: 10.1016/S0008-6363(99)00114-5 . PMID   10690334.
  88. ↑ "University Studies - Nitric Oxide Holds Promise for Diabetes". National Federation of the Blind (NFB).
  89. ↑ Griffiths MJ, Evans TW (December 2005). "Inhaled nitric oxide therapy in adults". The New England Journal of Medicine. 353 (25): 2683–2695. doi:10.1056/NEJMra051884. PMID   16371634. S2CID   28911682.
  90. 1 2 Abrams J (May 1996). "Beneficial actions of nitrates in cardiovascular disease". The American Journal of Cardiology. 77 (13): 31C–37C. doi:10.1016/S0002-9149(96)00186-5. PMID   8638524.
  91. ↑ Moro C, Leeds C, Chess-Williams R (January 2012). "Contractile activity of the bladder urothelium/lamina propria and its regulation by nitric oxide". European Journal of Pharmacology. 674 (2–3): 445–449. doi:10.1016/j.ejphar.2011.11.020. PMID   22119378.
  92. ↑ Andersson MC, Tobin G, Giglio D (April 2008). "Cholinergic nitric oxide release from the urinary bladder mucosa in cyclophosphamide-induced cystitis of the anaesthetized rat". British Journal of Pharmacology. 153 (7): 1438–1444. doi:10.1038/bjp.2008.6. PMC   2437908 . PMID   18246091.
  93. ↑ Summerfield DT, Desai H, Levitov A, Grooms DA, Marik PE (March 2012). "Inhaled nitric oxide as salvage therapy in massive pulmonary embolism: a case series". Respiratory Care. 57 (3): 444–448. doi: 10.4187/respcare.01373 . PMID   22005573.
  94. ↑ Katsnelson A (2020-05-20). "Multiple clinical trials test whether NO gas can treat and prevent COVID-19". Chemical & Engineering News . Retrieved 2020-07-14.
  95. ↑ Cohan A (2020-07-26). "Nitric oxide, a 'miracle molecule,' could treat or even prevent coronavirus, top doctors say". Boston Herald . Retrieved 2020-07-27.
  96. ↑ Gander K (2020-04-07). "What Is Nitric Oxide? How the Gas That Gave Us Viagra Could Help Treat Coronavirus Patients". Newsweek . Retrieved 2020-06-25.
  97. ↑ "Nitric Oxide Investigated as COVID-19 Treatment". WebMD. Retrieved 10 April 2020.
  98. ↑ Akerström S, Mousavi-Jazi M, Klingström J, Leijon M, Lundkvist A, Mirazimi A (February 2005). "Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus". Journal of Virology. 79 (3): 1966–1969. doi: 10.1128/JVI.79.3.1966-1969.2005 . PMC   544093 . PMID   15650225.
  99. 1 2 Powell A (2020-05-06). "Applying wisdom from the Himalayas to the ER's COVID battle". The Harvard Gazette . Retrieved 2020-06-25.
  100. ↑ "Lessons from the Backcountry in Finding a Potential COVID-19 Treatment". Massachusetts General Hospital. 2020-06-24. Retrieved 2020-06-25.
  101. ↑ "Inhaled Nitric Oxide Therapy for Emergency Room COVID-19 Patients". Massachusetts General Hospital. 2020-06-24. Retrieved 2020-06-25.
  102. ↑ Meredith S (2020-05-01). "How the gas that gave the world Viagra could help treat coronavirus patients". CNBC . Retrieved 2020-07-05.
  103. ↑ Riemer E (2020-06-23). "Tufts researchers test inhaled nitric oxide as COVID-19 treatment". WCVB-TV . Retrieved 2020-07-05.
  104. ↑ Martel J, Ko YF, Young JD, Ojcius DM (2020-05-06). "Could nasal nitric oxide help to mitigate the severity of COVID-19?". Microbes and Infection. 22 (4–5): 168–171. doi: 10.1016/j.micinf.2020.05.002 . PMC   7200356 . PMID   32387333.
  105. ↑ Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, Shainberg A (February 2006). "Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production". Molecular and Cellular Biochemistry. 283 (1–2): 75–83. doi:10.1007/s11010-006-2346-y. PMID   16444588. S2CID   24074568.
  106. ↑ González C, Herradón E, Abalo R, Vera G, Pérez-Nievas BG, Leza JC, et al. (May 2011). "Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS". Diabetes/Metabolism Research and Reviews. 27 (4): 331–340. doi:10.1002/dmrr.1176. PMID   21309057. S2CID   32450365.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.