Biological functions of nitric oxide explained

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

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.[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]

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 [6] [7]

A high salt intake attenuates NO production in patients with essential hypertension, although bioavailability remains unregulated.[8]

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.[9] 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.[10] 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.[11]

The nitrate-nitrite-nitric oxide pathway elevates nitric oxide through the sequential reduction of dietary nitrate derived from plant-based foods.[12] 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.[13] [14] 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.[15] 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.[16] Oral antiseptic mouthwash has been shown to eliminate the blood pressure lowering effects of dietary nitrate due to eradication of nitrate-reducing bacteria.[17]

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

Nasal breathing also produces nitric oxide within the body.[20] [21] [22] [23]

Immune response

Nitric oxide is generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response.[24] 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.[25] [26] [27] 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.[28] Nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania[29] and malaria;[30] [31] [32] the mechanism for this includes DNA damage[33] [34] [35] and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.[36]

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.[37] However, the role of ·NO in inflammation is complex with model studies involving viral infection suggesting that this gaseous mediator can also promote inflammation.[38]

In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.[39] 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.[40]

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.[41]

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.[42]

The iron-containing proteins ribonucleotide reductase and aconitase are deactivated by NO.[43] NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, a transcription factor in iNOS gene expression in response to inflammation.[44]

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.[45] 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.[46]

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.[7] Also a neurotransmitter, nitric oxide acts in the nitrergic neurons active on smooth muscle, abundant in the gastrointestinal tract and erectile tissue.[47] 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.[48]

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.[49] NO also plays a role in erection of the penis and clitoris.[50]

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.[51]

Effects on plants

In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase,[52] [53] [54] (although the existence of animal NOS homologs in plants is debated),[55] (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.[56] [57]

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.[58]

Nitric oxide sensing in plants is mediated by the N-end rule of proteolysis[59] [60] and controls abiotic stress responses such as flooding-induced hypoxia,[61] salt and drought stress.[62] [63] [64]

Nitric oxide interactions have been found within signaling pathways of plant hormones such as auxin,[65] ethylene,[61] [66] [67] Abscisic acid[59] and cytokinin.[68]

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.[69]

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.[70]

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.[71]

Medical uses

Drug Name:Nitric oxide
Width:121
Tradename:Inomax, Noxivent, Genosyl
Licence Eu:yes
Dailymedid:Nitric_oxide
Pregnancy Au:B2
Pregnancy Au Comment:[72]
Pregnancy Us:C
Routes Of Administration:Inhalation
Atc Prefix:R07
Atc Suffix:AX01
Legal Au:S4
Legal Us:Rx-only
Legal Status:Rx-only
Cas Number:10102-43-9
Pubchem:145068
Iuphar Ligand:2509
Drugbank:DB00435
Chemspiderid:127983
Unii:31C4KY9ESH
Kegg:D00074
Kegg2:C00533
Chebi:16480
Chembl:1200689
Iupac Name:Nitric oxide
N:1
O:1
Smiles:[N]=O
Stdinchi:1S/NO/c1-2
Stdinchikey:MWUXSHHQAYIFBG-UHFFFAOYSA-N

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

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.[73]

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.[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.[76] [77]

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.

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.

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.

Fatty liver disease

Nitric oxide production is associated with nonalcoholic fatty liver disease (NAFLD) and is essential for hepatic lipid metabolism under starvation.[78]

Lung infection

Nitric oxide is a potential therapeutic intervention in acute and chronic lung infections.[79] [80]

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.[81] 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.[82]

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.[83]

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.[84]

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[85] [86] 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.[87]

Pathology

People with diabetes usually have lower levels of nitric oxide than patients without diabetes.[88] 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.[89]

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.

Pharmacology

Nitric oxide is considered an antianginal 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.[90] 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,[91] [92] 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.[90]

Pulmonary embolism

Nitric oxide is also administered as salvage therapy in patients with acute right ventricular failure secondary to pulmonary embolism.[93]

Research

COVID-19

, studies and trials are underway that examine the possible benefits of nitric oxide in the treatment of COVID-19.[94] [95] [96] [97] This research is based on the fact that nitric oxide was investigated as an experimental therapy for SARS.[98] 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.[99] [100] He is involved in clinical trials which apply the use of inhaled nitric oxide as a treatment for COVID-19.[101] 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.[99] [102] According to WCVB-TV, similar trials are being conducted at Tufts Medical Center.[103] Other studies speculate that replacing mouth breathing (which decimates NO) with nasal breathing (which increases NO)[20] [21] [22] [23] 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."[104]

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.[105] The activation of mainly CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect of cannabinoids.[106]

Notes and References

  1. Hou YC, Janczuk A, Wang PG . Current trends in the development of nitric oxide donors . Current Pharmaceutical Design . 5 . 6 . 417–441 . June 1999 . 10390607 . 10.2174/138161280506230110111042 .
  2. Culotta E, Koshland DE . NO news is good news . Science . 258 . 5090 . 1862–1865 . December 1992 . 1361684 . 10.1126/science.1361684 . 1992Sci...258.1862C .
  3. Ignarro LJ . Nitric oxide. A novel signal transduction mechanism for transcellular communication . Hypertension . Dallas, Texas . 16 . 5 . 477–83 . November 1990 . 1977698 . 10.1161/01.hyp.16.5.477 . free .
  4. Web site: Weller R . Could the sun be good for your heart? . https://web.archive.org/web/20140216052804/http://www.ted.com/talks/richard_weller_could_the_sun_be_good_for_your_heart.html . 2014-02-16 . TedxGlasgow . January 2013 .
  5. Davies SA, Stewart EJ, Huesmann GR, Skaer NJ, Maddrell SH, Tublitz NJ, Dow JA . Neuropeptide stimulation of the nitric oxide signaling pathway in Drosophila melanogaster Malpighian tubules . The American Journal of Physiology . 273 . 2 Pt 2 . R823–R827 . August 1997 . 9277574 . 10.1152/ajpregu.1997.273.2.R823 .
  6. Book: Radicals for life: The various forms of nitric oxide . van Faassen E, Vanin A . Elsevier . Amsterdam . 2007 . 978-0-444-52236-8 .
  7. van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, Kozlov AV, Li H, Lundberg JO, Mason R, Nohl H, Rassaf T, Samouilov A, Slama-Schwok A, Shiva S, Vanin AF, Weitzberg E, Zweier J, Gladwin MT . 6 . Nitrite as regulator of hypoxic signaling in mammalian physiology . Medicinal Research Reviews . 29 . 5 . 683–741 . September 2009 . 19219851 . 2725214 . 10.1002/med.20151 .
  8. Osanai T, Fujiwara N, Saitoh M, Sasaki S, Tomita H, Nakamura M, Osawa H, Yamabe H, Okumura K . 6 . 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 . 2002 . 12207094 . 10.1159/000063555 . 46833231 .
  9. Liu AH, Bondonno CP, Croft KD, Puddey IB, Woodman RJ, Rich L, Ward NC, Vita JA, Hodgson JM . 6 . Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers . Nitric Oxide . 35 . 123–130 . November 2013 . 24120618 . 10.1016/j.niox.2013.10.001 .
  10. Lundberg JO, Weitzberg E, Gladwin MT . The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics . Nature Reviews. Drug Discovery . 7 . 2 . 156–167 . February 2008 . 18167491 . 10.1038/nrd2466 . 5141850 .
  11. Green SJ . Nitric oxide in mucosal immunity . Nature Medicine . 1 . 6 . 515–517 . June 1995 . 7585111 . 10.1038/nm0695-515 . 36184793 .
  12. Web site: Plant-based Diets | Plant-based Foods | Beetroot Juice | Nitric Oxide Vegetables . Berkeley Test . 2013-10-04 . dead . https://web.archive.org/web/20131004222229/http://www.berkeleytest.com/plant-based.html . 2013-10-04 .
  13. Ghosh SM, Kapil V, Fuentes-Calvo I, Bubb KJ, Pearl V, Milsom AB, Khambata R, Maleki-Toyserkani S, Yousuf M, Benjamin N, Webb AJ, Caulfield MJ, Hobbs AJ, Ahluwalia A . 6 . Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential . Hypertension . 61 . 5 . 1091–1102 . May 2013 . 23589565 . 10.1161/HYPERTENSIONAHA.111.00933 . free .
  14. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A . 6 . Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite . Hypertension . 51 . 3 . 784–790 . March 2008 . 18250365 . 2839282 . 10.1161/HYPERTENSIONAHA.107.103523 .
  15. Hezel MP, Weitzberg E . The oral microbiome and nitric oxide homoeostasis . Oral Diseases . 21 . 1 . 7–16 . January 2015 . 23837897 . 10.1111/odi.12157 . free .
  16. Web site: Green SJ . Turning DASH Strategy into Reality for Improved Cardio Wellness Outcomes: Part II . Real World Health Care . 2013-07-25 . 2013-10-04.
  17. Bryan NS, Tribble G, Angelov N . Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure . . 19 . 4 . 33 . 2017 . 10.1007/s11906-017-0725-2 . 28353075 .
  18. Suschek CV, Opländer C, van Faassen EE . Non-enzymatic NO production in human skin: effect of UVA on cutaneous NO stores . Nitric Oxide . 22 . 2 . 120–135 . February 2010 . 19879370 . 10.1016/j.niox.2009.10.006 .
  19. Opländer C, Römer A, Paunel-Görgülü A, Fritsch T, van Faassen EE, Mürtz M, Bozkurt A, Grieb G, Fuchs P, Pallua N, Suschek CV . 6 . Dermal application of nitric oxide in vivo: kinetics, biological responses, and therapeutic potential in humans . Clinical Pharmacology and Therapeutics . 91 . 6 . 1074–1082 . June 2012 . 22549282 . 10.1038/clpt.2011.366 . 32190689 .
  20. Web site: 'Nose breathing has more benefits than mouth breathing. 2020-07-09. Glazier E. 2019-11-04. The Times and Democrat.
  21. Web site: 'Mouth-breathing' gross, harmful to your health. 2020-06-28. Dahl M. 2011-01-11. NBC News.
  22. News: Could nasal breathing improve athletic performance?. 2020-05-31. Berman J . 2019-01-29. The Washington Post.
  23. Web site: Undiagnosed Mouth Breathing Creates Unhealthy Kids. 2020-05-31. Vinopal L. 2019-07-19. Fatherly.
  24. Green SJ, Mellouk S, Hoffman SL, Meltzer MS, Nacy CA . 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 . August 1990 . 2126524 . 10.1016/0165-2478(90)90083-3 .
  25. Book: Gorczynski RM, Stanley J . Clinical Immunology . 1999 . Landes Bioscience . Austin, TX . 978-1-57059-625-4 . 52342536 .
  26. Green SJ, Nacy CA, Schreiber RD, Granger DL, Crawford RM, Meltzer MS, Fortier AH . 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 . February 1993 . 8423095 . 302781 . 10.1128/IAI.61.2.689-698.1993 .
  27. Kamijo R, Gerecitano J, Shapiro D, Green SJ, Aguet M, Le J, Vilcek J . 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 . 1995 . 8832969 .
  28. Green SJ, Scheller LF, Marletta MA, Seguin MC, Klotz FW, Slayter M, Nelson BJ, Nacy CA . 6 . Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens . Immunology Letters . 43 . 1–2 . 87–94 . December 1994 . 7537721 . 10.1016/0165-2478(94)00158-8 . free . 2027.42/31140 .
  29. Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA . 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 . December 1990 . 2124240 . 10.4049/jimmunol.145.12.4290 . 21034574 .
  30. Seguin MC, Klotz FW, Schneider I, Weir JP, Goodbary M, Slayter M, Raney JJ, Aniagolu JU, Green SJ . 6 . 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 . July 1994 . 7516412 . 2191552 . 10.1084/jem.180.1.353 .
  31. Mellouk S, Green SJ, Nacy CA, Hoffman SL . 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 . June 1991 . 1903415 . 10.4049/jimmunol.146.11.3971 . 45487458 . free .
  32. Klotz FW, Scheller LF, Seguin MC, Kumar N, Marletta MA, Green SJ, Azad AF . 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 . April 1995 . 7534796 . 10.4049/jimmunol.154.7.3391 . 12612236 . free .
  33. Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS . 6 . DNA deaminating ability and genotoxicity of nitric oxide and its progenitors . Science . 254 . 5034 . 1001–1003 . November 1991 . 1948068 . 10.1126/science.1948068 . 1991Sci...254.1001W .
  34. Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR . 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 . April 1992 . 1557408 . 48797 . 10.1073/pnas.89.7.3030 . free . 1992PNAS...89.3030N . Free text.
  35. Li CQ, Pang B, Kiziltepe T, Trudel LJ, Engelward BP, Dedon PC, Wogan GN . 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 . March 2006 . 16544944 . 2570754 . 10.1021/tx050283e . free text
  36. Hibbs JB, Taintor RR, Vavrin Z, Rachlin EM . Nitric oxide: a cytotoxic activated macrophage effector molecule . Biochemical and Biophysical Research Communications . 157 . 1 . 87–94 . November 1988 . 3196352 . 10.1016/S0006-291X(88)80015-9 .
  37. Wallace JL, Ianaro A, Flannigan KL, Cirino G . Gaseous mediators in resolution of inflammation . Seminars in Immunology . 27 . 3 . 227–233 . May 2015 . 26095908 . 10.1016/j.smim.2015.05.004 .
  38. Uehara EU, Shida BD, de Brito CA . Role of nitric oxide in immune responses against viruses: beyond microbicidal activity . Inflammation Research . 64 . 11 . 845–852 . November 2015 . 26208702 . 10.1007/s00011-015-0857-2 . 14587150 .
  39. Book: Janeway, C. A. . Immunobiology: the immune system in health and disease . Garland Science . New York . 2005 . 6th . 978-0-8153-4101-7 . etal.
  40. Jacobs L, Nawrot TS, de Geus B, Meeusen R, Degraeuwe B, Bernard A, Sughis M, Nemery B, Panis LI . 6 . Subclinical responses in healthy cyclists briefly exposed to traffic-related air pollution: an intervention study . Environmental Health . 9 . 64 . 64 . October 2010 . 20973949 . 2984475 . 10.1186/1476-069X-9-64 . free . 2010EnvHe...9...64J .
  41. Book: van Faassen E, Vanin A . 2007 . Radicals for life: The various forms of nitric oxide . Elsevier . Amsterdam . 978-0-444-52236-8.
  42. Book: van Faassen E, Vanin A . 2004 . Nitric Oxide . Encyclopedia of Analytical Science . 2nd . Elsevier . 978-0-12-764100-3 .
  43. Shami PJ, Moore JO, Gockerman JP, Hathorn JW, Misukonis MA, Weinberg JB . Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells . Leukemia Research . 19 . 8 . 527–533 . August 1995 . 7658698 . 10.1016/0145-2126(95)00013-E .
  44. Kaibori M, Sakitani K, Oda M, Kamiyama Y, Masu Y, Nishizawa M, Ito S, Okumura T . 6 . 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 . June 1999 . 10406194 . 10.1016/S0168-8278(99)80270-0 .
  45. Book: Derbyshire ER, Marletta MA . Biochemistry of Soluble Guanylate Cyclase . CGMP: Generators, Effectors and Therapeutic Implications . 2009 . 191 . . 17–31. 10.1007/978-3-540-68964-5_2. 19089323 . Handbook of Experimental Pharmacology . 978-3-540-68960-7 . 25597341 .
  46. Book: 2003. Rhoades RA, Tanner GA . Medical physiology . 2nd.
  47. Toda N, Ayajiki K, Okamura T . Nitric oxide and penile erectile function . Pharmacology & Therapeutics . 106 . 2 . 233–266 . May 2005 . 15866322 . 10.1016/j.pharmthera.2004.11.011 .
  48. Dessy C, Feron O . Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature . 10.2174/1568014043355348 . Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents . 3 . 3 . 207–216 . 2004 .
  49. Yoon Y, Song J, Hong SH, Kim JQ . Plasma nitric oxide concentrations and nitric oxide synthase gene polymorphisms in coronary artery disease . Clinical Chemistry . 46 . 10 . 1626–1630 . October 2000 . 11017941 . 10.1093/clinchem/46.10.1626 . free .
  50. Gragasin FS, Michelakis ED, Hogan A, Moudgil R, Hashimoto K, Wu X, Bonnet S, Haromy A, Archer SL . 6 . The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels . FASEB Journal . 18 . 12 . 1382–1391 . September 2004 . 15333581 . 10.1096/fj.04-1978com . free . 45447939 .
  51. Thakur NK, Hayashi T, Sumi D, Kano H, Matsui-Hirai H, Tsunekawa T, Iguchi A . Anti-atherosclerotic effect of beta-blocker with nitric oxide-releasing action on the severe atherosclerosis . Journal of Cardiovascular Pharmacology . 39 . 2 . 298–309 . February 2002 . 11791016 . 10.1097/00005344-200202000-00017 . 24712179 . free .
  52. Corpas FJ, Barroso JB, Carreras A, Quirós M, León AM, Romero-Puertas MC, Esteban FJ, Valderrama R, Palma JM, Sandalio LM, Gómez M, del Río LA . 6 . Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea plants . Plant Physiology . 136 . 1 . 2722–2733 . September 2004 . 15347796 . 523336 . 10.1104/pp.104.042812 .
  53. Corpas FJ, Barroso JB, Carreras A, Valderrama R, Palma JM, León AM, Sandalio LM, del Río LA . 6 . Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development . Planta . 224 . 2 . 246–254 . July 2006 . 16397797 . 10.1007/s00425-005-0205-9 . 2006Plant.224..246C . 23329722 .
  54. Valderrama R, Corpas FJ, Carreras A, Fernández-Ocaña A, Chaki M, Luque F, Gómez-Rodríguez MV, Colmenero-Varea P, Del Río LA, Barroso JB . 6 . Nitrosative stress in plants . FEBS Letters . 581 . 3 . 453–461 . February 2007 . 17240373 . 10.1016/j.febslet.2007.01.006 . 34725559 . free . 2007FEBSL.581..453V .
  55. Corpas FJ, Barroso JB, Del Río LA . Enzymatic sources of nitric oxide in plant cells – beyond one protein–one function. New Phytologist. 162. 2. 246–7. 2004. 10.1111/j.1469-8137.2004.01058.x . free.
  56. Tuffs A . Max-Planck Society investigates misconduct . BMJ . 319 . 7205 . 274 . July 1999 . 10426722 . 1126920 . 10.1136/bmj.319.7205.274a .
  57. Mur LA, Mandon J, Persijn S, Cristescu SM, Moshkov IE, Novikova GV, Hall MA, Harren FJ, Hebelstrup KH, Gupta KJ . 6 . Nitric oxide in plants: an assessment of the current state of knowledge . AoB Plants . 5 . pls052 . 2013 . 23372921 . 3560241 . 10.1093/aobpla/pls052 .
  58. Verma K, Mehta SK, Shekhawat GS . 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 . April 2013 . 23322177 . 10.1007/s10534-013-9608-4 . 254285519 .
  59. Gibbs DJ, Md Isa N, Movahedi M, Lozano-Juste J, Mendiondo GM, Berckhan S, Marín-de la Rosa N, Vicente Conde J, Sousa Correia C, Pearce SP, Bassel GW, Hamali B, Talloji P, Tomé DF, Coego A, Beynon J, Alabadí D, Bachmair A, León J, Gray JE, Theodoulou FL, Holdsworth MJ . 6 . Nitric oxide sensing in plants is mediated by proteolytic control of group VII ERF transcription factors . Molecular Cell . 53 . 3 . 369–379 . February 2014 . 24462115 . 3969242 . 10.1016/j.molcel.2013.12.020 . free .
  60. León J, Costa-Broseta Á, Castillo MC . 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 . May 2020 . 32052059 . 7260729 . 10.1093/jxb/eraa069 . free .
  61. Hartman S, Liu Z, van Veen H, Vicente J, Reinen E, Martopawiro S, Zhang H, van Dongen N, Bosman F, Bassel GW, Visser EJ, Bailey-Serres J, Theodoulou FL, Hebelstrup KH, Gibbs DJ, Holdsworth MJ, Sasidharan R, Voesenek LA . 6 . Ethylene-mediated nitric oxide depletion pre-adapts plants to hypoxia stress . Nature Communications . 10 . 1 . 4020 . September 2019 . 31488841 . 6728379 . 10.1038/s41467-019-12045-4 . free . 2019NatCo..10.4020H .
  62. Vicente J, Mendiondo GM, Movahedi M, Peirats-Llobet M, Juan YT, Shen YY, Dambire C, Smart K, Rodriguez PL, Charng YY, Gray JE, Holdsworth MJ . 6 . The Cys-Arg/N-End Rule Pathway Is a General Sensor of Abiotic Stress in Flowering Plants . Current Biology . 27 . 20 . 3183–3190.e4 . October 2017 . 29033328 . 5668231 . 10.1016/j.cub.2017.09.006 . free . 2017CBio...27E3183V .
  63. Castillo MC, Costa-Broseta Á, Gayubas B, León J . NIN-like protein7 and PROTEOLYSIS6 functional interaction enhances tolerance to sucrose, ABA, and submergence . Plant Physiology . 187 . 4 . 2731–2748 . December 2021 . 34618055 . 8644111 . 10.1093/plphys/kiab382 .
  64. Hartman S . NIN-like Protein7 is controlled by oxygen and nitric oxide and contributes to stress tolerance through PROTEOLYSIS6 . Plant Physiology . 187 . 4 . 2346–2347 . December 2021 . 34890464 . 8644194 . 10.1093/plphys/kiab415 .
  65. Terrile MC, París R, Calderón-Villalobos LI, Iglesias MJ, Lamattina L, Estelle M, Casalongué CA . Nitric oxide influences auxin signaling through S-nitrosylation of the Arabidopsis TRANSPORT INHIBITOR RESPONSE 1 auxin receptor . The Plant Journal . 70 . 3 . 492–500 . May 2012 . 22171938 . 3324642 . 10.1111/j.1365-313X.2011.04885.x .
  66. Melo NK, Bianchetti RE, Lira BS, Oliveira PM, Zuccarelli R, Dias DL, Demarco D, Peres LE, Rossi M, Freschi L . 6 . Nitric Oxide, Ethylene, and Auxin Cross Talk Mediates Greening and Plastid Development in Deetiolating Tomato Seedlings . Plant Physiology . 170 . 4 . 2278–2294 . April 2016 . 26829981 . 4825133 . 10.1104/pp.16.00023 . free .
  67. Zhang L, Li G, Wang M, Di D, Sun L, Kronzucker HJ, Shi W . 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 . July 2018 . 29658100 . 10.1111/nph.15157 . free . 11343/283842 . free .
  68. Liu WZ, Kong DD, Gu XX, Gao HB, Wang JZ, Xia M, Gao Q, Tian LL, Xu ZH, Bao F, Hu Y, Ye NS, Pei ZM, He YK . 6 . 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 . January 2013 . 23319631 . 3557067 . 10.1073/pnas.1213235110 . free . 2013PNAS..110.1548L .
  69. Encyclopedia: Hogan CM . 2010 . Abiotic factor . https://web.archive.org/web/20130608071757/http://www.eoearth.org/article/Abiotic_factor?topic=49461 . June 8, 2013 . . Monosson E, Cleveland C . . Washington DC .
  70. Walker FA . Nitric oxide interaction with insect nitrophorins and thoughts on the electron configuration of the 6 complex . Journal of Inorganic Biochemistry . 99 . 1 . 216–236 . January 2005 . 15598503 . 10.1016/j.jinorgbio.2004.10.009 .
  71. Patel BA, Moreau M, Widom J, Chen H, Yin L, Hua Y, Crane BR . 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 . October 2009 . 19841256 . 2775278 . 10.1073/pnas.0907262106 . free . 2009PNAS..10618183P .
  72. Web site: Nitric oxide Use During Pregnancy . Drugs.com . 21 November 2019 . 29 May 2020.
  73. Web site: Inomax- nitric oxide gas . DailyMed . U.S. National Library of Medicine . 25 February 2019 . 29 May 2020.
  74. Web site: Inomax EPAR . European Medicines Agency (EMA) . 17 September 2018 . 29 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  75. Web site: Drug Approval Package: Inomax (Nitric Oxide) NDA# 20-845 . U.S. Food and Drug Administration (FDA) . 31 March 2001 . 29 May 2020.
  76. Wiklund M, Granswed I, Nyman G . Pulsed inhaled nitric oxide improves arterial oxygenation in colic horses undergoing abdominal surgery . Veterinary Anaesthesia and Analgesia . 44 . 5 . 1139–1148 . September 2017 . 29051000 . 10.1016/j.vaa.2016.11.015 .
  77. Wiklund M, Kellgren M, Wulcan S, Grubb T, Nyman G . 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 . January 2020 . 31009091 . 10.1111/evj.13129 . 128175609 .
  78. Gu Q, Yang X, Lin L, Li S, Li Q, Zhong S, Peng J, Cui Z . 6 . Genetic ablation of solute carrier family 7a3a leads to hepatic steatosis in zebrafish during fasting . Hepatology . 60 . 6 . 1929–1941 . December 2014 . 25130427 . 10.1002/hep.27356 . 205894350 . free .
  79. Fang FC . Antimicrobial reactive oxygen and nitrogen species: concepts and controversies . Nature Reviews. Microbiology . 2 . 10 . 820–832 . October 2004 . 15378046 . 10.1038/nrmicro1004 . 11063073 .
  80. Goldfarb RD, Cinel I . Inhaled nitric oxide therapy for sepsis: more than just lung . Critical Care Medicine . 35 . 1 . 290–292 . January 2007 . 17197767 . 10.1097/01.CCM.0000251290.41866.2B .
  81. Lipina C, Hundal HS . The endocannabinoid system: 'NO' longer anonymous in the control of nitrergic signalling? . Journal of Molecular Cell Biology . 9 . 2 . 91–103 . April 2017 . 28130308 . 5439392 . 10.1093/jmcb/mjx008 .
  82. Krawutschke C, Koesling D, Russwurm M . Cyclic GMP in Vascular Relaxation: Export Is of Similar Importance as Degradation . Arteriosclerosis, Thrombosis, and Vascular Biology . 35 . 9 . 2011–2019 . September 2015 . 26205960 . 10.1161/ATVBAHA.115.306133 . free .
  83. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, Sekar KC, Auten RL, Bhutani VK, Gerdes JS, George TN, Southgate WM, Carriedo H, Couser RJ, Mammel MC, Hall DC, Pappagallo M, Sardesai S, Strain JD, Baier M, Abman SH . 6 . Early inhaled nitric oxide therapy in premature newborns with respiratory failure . The New England Journal of Medicine . 355 . 4 . 354–364 . July 2006 . 16870914 . 10.1056/NEJMoa060442 . 10.1.1.319.6088 .
  84. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, Walsh MC, Durand DJ, Mayock DE, Eichenwald EC, Null DR, Hudak ML, Puri AR, Golombek SG, Courtney SE, Stewart DL, Welty SE, Phibbs RH, Hibbs AM, Luan X, Wadlinger SR, Asselin JM, Coburn CE . 6 . Inhaled nitric oxide in preterm infants undergoing mechanical ventilation . The New England Journal of Medicine . 355 . 4 . 343–353 . July 2006 . 16870913 . 10.1056/NEJMoa061088 . free .
  85. Barrington KJ, Finer N, Pennaforte T, Altit G . Nitric oxide for respiratory failure in infants born at or near term . The Cochrane Database of Systematic Reviews . 1 . 1 . CD000399 . January 2017 . 28056166 . 6464941 . 10.1002/14651858.CD000399.pub3 .
  86. Chotigeat U, Khorana M, Kanjanapattanakul W . Inhaled nitric oxide in newborns with severe hypoxic respiratory failure . Journal of the Medical Association of Thailand = Chotmaihet Thangphaet . 90 . 2 . 266–271 . February 2007 . 17375630 .
  87. Hayward CS, Kelly RP, Macdonald PS . Inhaled nitric oxide in cardiology practice . Cardiovascular Research . 43 . 3 . 628–638 . August 1999 . 10690334 . 10.1016/S0008-6363(99)00114-5 . free .
  88. Web site: University Studies - Nitric Oxide Holds Promise for Diabetes . National Federation of the Blind (NFB) .
  89. Griffiths MJ, Evans TW . Inhaled nitric oxide therapy in adults . The New England Journal of Medicine . 353 . 25 . 2683–2695 . December 2005 . 16371634 . 10.1056/NEJMra051884 . 28911682 .
  90. Abrams J . Beneficial actions of nitrates in cardiovascular disease . The American Journal of Cardiology . 77 . 13 . 31C–37C . May 1996 . 8638524 . 10.1016/S0002-9149(96)00186-5 .
  91. Moro C, Leeds C, Chess-Williams R . Contractile activity of the bladder urothelium/lamina propria and its regulation by nitric oxide . European Journal of Pharmacology . 674 . 2–3 . 445–449 . January 2012 . 22119378 . 10.1016/j.ejphar.2011.11.020 .
  92. Andersson MC, Tobin G, Giglio D . 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 . April 2008 . 18246091 . 2437908 . 10.1038/bjp.2008.6 .
  93. Summerfield DT, Desai H, Levitov A, Grooms DA, Marik PE . Inhaled nitric oxide as salvage therapy in massive pulmonary embolism: a case series . Respiratory Care . 57 . 3 . 444–448 . March 2012 . 22005573 . 10.4187/respcare.01373 . free .
  94. Multiple clinical trials test whether NO gas can treat and prevent COVID-19 . 2020-07-14 . Katsnelson A . 2020-05-20 . .
  95. Web site: Nitric oxide, a 'miracle molecule,' could treat or even prevent coronavirus, top doctors say. 2020-07-27. Cohan A. 2020-07-26. Boston Herald.
  96. What Is Nitric Oxide? How the Gas That Gave Us Viagra Could Help Treat Coronavirus Patients . 2020-06-25 . Gander K . 2020-04-07 . .
  97. Web site: Nitric Oxide Investigated as COVID-19 Treatment . WebMD . 10 April 2020 . en.
  98. Akerström S, Mousavi-Jazi M, Klingström J, Leijon M, Lundkvist A, Mirazimi A . Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus . Journal of Virology . 79 . 3 . 1966–1969 . February 2005 . 15650225 . 544093 . 10.1128/JVI.79.3.1966-1969.2005 . free .
  99. Web site: Applying wisdom from the Himalayas to the ER's COVID battle. 2020-06-25. Powell A . 2020-05-06. The Harvard Gazette.
  100. Web site: Lessons from the Backcountry in Finding a Potential COVID-19 Treatment. 2020-06-25. 2020-06-24. Massachusetts General Hospital.
  101. Web site: Inhaled Nitric Oxide Therapy for Emergency Room COVID-19 Patients. 2020-06-25. 2020-06-24. Massachusetts General Hospital.
  102. Web site: How the gas that gave the world Viagra could help treat coronavirus patients. 2020-07-05. Meredith S . 2020-05-01. CNBC.
  103. Web site: Tufts researchers test inhaled nitric oxide as COVID-19 treatment. 2020-07-05. Riemer E. 2020-06-23. WCVB-TV.
  104. Martel J, Ko YF, Young JD, Ojcius DM . Could nasal nitric oxide help to mitigate the severity of COVID-19? . Microbes and Infection . 22 . 4–5 . 168–171 . 2020-05-06 . 32387333 . 7200356 . 10.1016/j.micinf.2020.05.002 . free .
  105. Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, Shainberg A . 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 . February 2006 . 16444588 . 10.1007/s11010-006-2346-y . 24074568 .
  106. González C, Herradón E, Abalo R, Vera G, Pérez-Nievas BG, Leza JC, Martín MI, López-Miranda V . 6 . 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 . May 2011 . 21309057 . 10.1002/dmrr.1176 . 32450365 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Biological functions of nitric oxide".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.