Biological functions of nitric oxide are roles thatnitric oxide plays within biology.
Nitric oxide (nitrogen monoxide) is amolecule andchemical compound withchemical formula ofNO. In mammals including humans, nitric oxide is asignaling 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 asnitroglycerine andamyl nitrite are precursors to nitric oxide. Low levels of nitric oxide production are typically due toischemic damage in the liver.
Nitric oxide synthases (NOSs) synthesize the metastable free radical nitric oxide (NO). Threeisoforms 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 arterialvasodilation 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).[6]
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 reactionsin vivo.Nitroglycerin andamyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. The vasodilating antihypertensive drugminoxidil contains an ·NO moiety and may act as an NO agonist. Likewise,Sildenafil citrate, popularly known by the trade nameViagra, 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]
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 ofnitrate.[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 abiofilm 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 asspinach andarugula, andbeetroot, 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 (bynitrate reductase, a bacterial enzyme) occurs in the mouth, by commensal bacteria, an obligatory and necessary step.[16] Monitoring nitric oxide status bysaliva 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 theDASH diet.[17] Oralantisepticmouthwash 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.[19] In alternative fashion, nitrite anions on sun-exposed skin may be photolyzed to free nitric oxide radicals by UVA in sunlight.[20] This mechanism may elicit significant changes to the systemic blood circulation in humans and be exploited for therapeutic purposes.[21]
S-nitrosation involves the (reversible) conversion ofthiol groups, includingcysteine 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.[22]
Nitric oxide to a transition metal ion like iron or copper, formingmetal 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.[23]
The iron-containing proteinsribonucleotide reductase andaconitase are deactivated by NO.[24] NO has been demonstrated to activateNF-κB in peripheral blood mononuclear cells, Jim a transcription factor in iNOS gene expression in response to inflammation.[25]
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.[26] Cyclic-GMP activatesprotein 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 thecross-bridge cycle and leading to relaxation of the smooth muscle cell.[27]
Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans withatherosclerosis,diabetes, orhypertension often show impaired NO pathways.[29]
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 ofextracellular fluid homeostasis and is essential for the regulation of blood flow and blood pressure.[30] NO also plays a role inerection of the penis andclitoris.[31]
Nitric oxide also acts oncardiac muscle to decrease contractility andheart 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.[32]
Nitric oxide is generated byphagocytes (monocytes,macrophages, andneutrophils) as part of the humanimmune response.[34] Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated byinterferon-gamma (IFN-γ) as a single signal or bytumor necrosis factor (TNF) along with a second signal.[35][36][37] On the other hand,transforming growth factor-beta (TGF-β) provides a strong inhibitory signal to iNOS, whereasinterleukin-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.[38] Nitric oxide is secreted asfree radicals in an immune response and is toxic to bacteria and intracellular parasites, includingLeishmania[39] andmalaria;[40][41][42] the mechanism for this includes DNA damage[43][44][45] and degradation of iron sulfur centers into iron ions andiron-nitrosyl compounds.[46]
The inducible pathway (iNOS) of nitrogen oxide synthesis in phagocytes can generate large amounts of NO that triggerapoptosis 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 tospecialized pro-resolving mediators to dampen and reverse inflammatory responses by neutralizing and then speeding the clearance of pro-inflammatory cells from inflamed tissues.[47] However, the role of·NO in inflammation is complex with model studies involving viral infection suggesting that this gaseous mediator can also promote inflammation.[48]
In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.[49] Because nitric oxide might serve as aninflammometer (meter of inflammation) in conditions likeasthma, interest has increased in the use ofexhaled nitric oxide as abreath test in diseases withairway 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.[50]
While nitric oxide is typically known to halt bacterial growth as part of an immune response, in one case NO protects a bacterium. The bacteriumDeinococcus 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.[51]
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 NOShomologs in plants is debated),[55] (ii) plasma membrane-boundnitrate reductase, (iii) mitochondrial electron transport chain, or (iv) non-enzymatic reactions. It is a signaling molecule, acts mainly againstoxidative stress and also plays a role in plant pathogen interactions. Treatingcut flowers and other plants with nitric oxide has been shown to lengthen the time before wilting.[56][57]
Blood-sucking insects exploit vasodilation induced by NO to ensure their blood meal. These insects includeCimex lectularius (bed bug) andRhodnius proxlixus (kissing bug). These insects deliver NO from its carriernitrophorin, which is found in their saliva.[6]
In the European Union, nitric oxide in conjunction with ventilatory support and other appropriate active substances, is indicated:[71]
for the treatment of newborn infants ≥34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need forextracorporeal membrane oxygenation (ECMO);[71]
as part of the treatment of peri- and post-operative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0–17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation.[71]
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.[72]
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).[71]
Nitric oxide was approved for medical use in the United States in December 1999 and for medical use in the European Union in 2001.[73][71][72]
Nitric oxide/oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat primarypulmonary hypertension in neonatal patients[74][75] and post-meconium aspiration related to birth defects. These are often a last-resort gas mixture before the use ofextracorporeal 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.[76]
The primary use is in the form ofnitroglycerin, either pill or liquid spray forms, which, as a prodrug, isdenitrated 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 forneonates. In the adult ICU setting, inhaled ·NO can improve hypoxemia inacute lung injury,acute respiratory distress syndrome, and severepulmonary 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.[77]
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.[79][80]
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 inmethemoglobin and pulmonary toxicities associated with inspired ·NO. Elevated NO may causeacute lung injury.[citation needed]
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]
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]
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]
Nitric oxide is a cell signaling molecule produced by many cells of the body, and growing evidence suggests that the biological actions of theendocannabinoid 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, activatingguanylate cyclase and increasing intracellular levels ofcyclic-guanosine 3',5'-monophosphate (cGMP). The elevation of intracellular cGMP results in relaxation by the activation ofcGMP-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 thepartial 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]
Nitric oxide is considered anantianginal 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.[85] Nitric oxide can contribute toreperfusion injury when an excessive amount produced during reperfusion (following a period ofischemia) reacts withsuperoxide to produce the damaging oxidantperoxynitrite. In contrast, inhaled nitric oxide has been shown to help survival and recovery fromparaquat 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 asulfhydryl 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,[86][87] 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.[85]
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 developneuropathy and non-healing ulcers, and to be at a greater risk for lower limbamputation.
Nitric oxide production is associated with nonalcoholic fatty liver disease (NAFLD) and is essential for hepatic lipid metabolism under starvation.[89]
As of April 2020[update], studies and trials are underway that examine the possible benefits of nitric oxide in the treatment ofCOVID-19.[92][93][94][95] This research is based on the fact that nitric oxide was investigated as an experimental therapy forSARS.[96] Brian Strickland, MD, a fellow inWilderness Medicine atMassachusetts General Hospital who studies "acute respiratory distress" in high altitudes, is applying this research towards COVID-19.[97][98] He is involved in clinical trials which apply the use of inhaled nitric oxide as a treatment for COVID-19.[99] This approach was inspired by the work of associate professor of emergency medicine at theHarvard Medical School N. Stuart Harris, who has been studying the effects ofaltitude sickness on mountain climbers, such as those who climbMount 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.[97][100] According toWCVB-TV, similar trials are being conducted atTufts Medical Center.[101] Other studies speculate that replacingmouth breathing (which decimates NO) withnasal breathing (which increases NO)[102][103][104][105] 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."[106]
^abHou YC, Janczuk A, Wang PG (June 1999). "Current trends in the development of nitric oxide donors".Current Pharmaceutical Design.5 (6):417–441.doi:10.2174/138161280506230110111042.PMID10390607.
^Davies SA, Stewart EJ, Huesmann GR, Skaer NJ, Maddrell SH, Tublitz NJ, et al. (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.PMID9277574.
^abWalker 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.PMID15598503.
^van Faassen E, Vanin A, eds. (2007).Radicals for life: The various forms of nitric oxide. Amsterdam: Elsevier.ISBN978-0-444-52236-8.
^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.PMID12207094.S2CID46833231.
^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.PMID24120618.
^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.PMID18167491.S2CID5141850.
^Weller R, Pattullo S, Smith L, Golden M, Ormerod A, Benjamin N (September 1996). "Nitric oxide is generated on the skin surface by reduction of sweat nitrate".The Journal of Investigative Dermatology.107 (3):327–331.doi:10.1111/1523-1747.ep12363167.PMID8751965.
^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.PMID19879370.
^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.PMID22549282.S2CID32190689.
^van Faassen E, Vanin A (2007).Radicals for life: The various forms of nitric oxide. Amsterdam: Elsevier.ISBN978-0-444-52236-8.
^van Faassen E, Vanin A (2004). "Nitric Oxide".Encyclopedia of Analytical Science (2nd ed.). Elsevier.ISBN978-0-12-764100-3.
^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.PMID7658698.
^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.PMID10406194.
^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.
^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.PMID26197209.
^Kamijo R, Gerecitano J, Shapiro D, Green SJ, Aguet M, Le J, et al. (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.PMID8832969.
^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.PMID7537721.
^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.PMID2124240.S2CID21034574.
^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.PMID1948068.
^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.PMID3196352.
^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.PMID26095908.
^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.PMID26208702.S2CID14587150.
^Janeway, C. A., et al. (2005).Immunobiology: the immune system in health and disease (6th ed.). New York: Garland Science.ISBN978-0-8153-4101-7.
^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.PMID16397797.S2CID23329722.
^abcde"Inomax EPAR".European Medicines Agency (EMA). 17 September 2018. Retrieved29 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ab"Inomax- nitric oxide gas".DailyMed. U.S. National Library of Medicine. 25 February 2019. Retrieved29 May 2020.
^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.PMID17375630.
^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.PMID29051000.
^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.PMID31009091.S2CID128175609.
^abAbrams 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.PMID8638524.
^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.PMID22119378.
^Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, et al. (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.PMID16444588.S2CID24074568.
^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.PMID21309057.S2CID32450365.
