Biological functions of nitric oxide
Biological functions of nitric oxide are roles that nitric oxide plays within biology.
As a consequence of its importance in
Sources of nitric oxide
Nitric oxide biosynthesis
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.
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.
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
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.[38] However, the role of ·NO in inflammation is complex with model studies involving viral infection suggesting that this gaseous mediator can also promote inflammation.[39]
In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.
Molecular effects of NO on biological systems
In cells, two broad classes of reactions of nitric oxide involve the S-
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.[42]
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.[43]
The iron-containing proteins ribonucleotide reductase and aconitase are deactivated by NO.[44] NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, a transcription factor in iNOS gene expression in response to inflammation.[45]
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.
Vasodilation and smooth muscles
Nitric oxide
.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.[49]
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.
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.[52]
Effects on plants
In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase,
In plants, NO also regulates some
Nitric oxide sensing in plants is mediated by the N-end rule of proteolysis[60][61] and controls abiotic stress responses such as flooding-induced hypoxia,[62] salt and drought stress.[63][64][65]
Nitric oxide interactions have been found within signaling pathways of
Atmospheric nitric oxide can enter the
Effects in insects
Blood-sucking insects exploit vasodilation induced by NO to ensure their blood meal. These insects include Cimex lectularius (
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
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In the European Union nitric oxide in conjunction with ventilatory support and other appropriate active substances, is indicated:[73]
- 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 for extracorporeal membrane oxygenation (ECMO);[73]
- 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.[73]
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.[74]
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).[73]
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][73][74]
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.[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
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
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
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.
Pediatric and adult use
The primary use is in the form of
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
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
Research
COVID‑19
As of April 2020[update], studies and trials are underway that examine the possible benefits of nitric oxide in the treatment of
Cardiac protection
It is found, that the naturally occurring
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