seminar presentation on nitric oxide

Nitric Oxide

Molecular mechanisms of nitric oxide signaling in health and disease, conference description.

The Nitric Oxide GRC is a premier, international scientific conference focused on advancing the frontiers of science through the presentation of cutting-edge and unpublished research, prioritizing time for discussion after each talk and fostering informal interactions among scientists of all career stages. The conference program includes a diverse range of speakers and discussion leaders from institutions and organizations worldwide, concentrating on the latest developments in the field. The conference is five days long and held in a remote location to increase the sense of camaraderie and create scientific communities, with lasting collaborations and friendships. In addition to premier talks, the conference has designated time for poster sessions from individuals of all career stages, and afternoon free time and communal meals allow for informal networking opportunities with leaders in the field.

In this first Nitric Oxide focused meeting since the pandemic we will focus on the role that NO plays both in health and disease. Furthermore, we will examine the molecular mechanisms that regulate these functions. Topics will range from the role of NO in pulmonary function and COVID itself to optimal function with tissues such as skeletal muscle. Our goal is to create a diverse atmosphere and vibrant discussion that will lead to advances in the field and encourage the development of young and old scientists alike in the field of nitric oxide biology and chemistry.

Related Meeting

This GRC will be held in conjunction with the "Nitric Oxide" Gordon Research Seminar (GRS). Those interested in attending both meetings must submit an application for the GRS in addition to an application for the GRC. Refer to the associated GRS program page for more information.

Conference Program

Contributors.

Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R13HL167550. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

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While the number of people affected by autoimmune disease increases every year, most cases are not diagnosed and continue to progress. This informative seminar, developed by Dr. Datis Kharrazian, will review the protective and destructive roles of nitric oxide and glutathione (GSH) in autoimmune reactions.

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Nitric Oxide: From Research to Therapeutics pp 223–248 Cite as

Nitric Oxide as a Diagnostic and Therapeutic Tool in Respiratory Diseases

• Kavita Gulati 16 ,
• Suresh Kumar Thokchom 16 &
• Arunabha Ray 17  
• First Online: 08 March 2023

338 Accesses

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 22))

Nitric oxide (NO) is a gasotransmitter that plays a vital role in diverse biological processes. NO is a fundamental component in regulating cardiovascular functions, smooth muscle tone, and neurotransmission. It acts as a critical signaling molecule in the body that widens blood vessels in the lungs when inhaled. Several lines of evidence indicate that endogenous NO is responsible for the physiological regulation of airways and is involved in various respiratory diseases. The primary sources of NO in the respiratory tract are epithelial cells, inflammatory cells (macrophages, neutrophils, mast cells), and endothelial. The highest output of NO is from epithelial cells and macrophages. The concentrations of NO are different for each airway inflammatory disease, and these changes in the level help in the evaluation and management of respiratory disorders. The amount of NO found in expired air is detectable by a non-invasive method in animals and humans. Several research findings have pointed out the role of NO in the pathogenesis of various diseases affecting airways, and this can be translated to future application in clinical practice. This review summarizes the basic understanding of NO in various respiratory disorders, and the fractional exhaled levels of NO can be an important non-invasive economical diagnostic marker. Further, the current version of the role of endogenous NO may provide new insight into the regulation of the airways, and inhaled NO may potentially contribute as treatment strategies to various respiratory diseases in clinical practice.

• Nitric oxide
• Respiratory diseases

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Gulati, K., Thokchom, S.K., Ray, A. (2023). Nitric Oxide as a Diagnostic and Therapeutic Tool in Respiratory Diseases. In: Ray, A., Gulati, K. (eds) Nitric Oxide: From Research to Therapeutics. Advances in Biochemistry in Health and Disease, vol 22. Springer, Cham. https://doi.org/10.1007/978-3-031-24778-1_11

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Nitric Oxide: Everything You Need to Know

Uses of nitric oxide, nitric oxide deficiency.

• Side Effects

Precautions

Interactions, similar supplements, frequently asked questions.

Nitric oxide (NO) is a naturally occurring gas. NO can relax your blood vessels to increase blood flow in your body.

NO supplements, on the other hand, don't have actual NO gas. Instead, the supplements typically contain substances that the body may use and convert to NO. These substances are amino acids—like L-arginine and L-citrulline —and nitrates (NO 3 ).

Amino acids are the building blocks of proteins , and can be found in food. In your body, L-citrulline is converted into L-arginine before becoming NO. When you take L-citrulline, it doesn't break down by the liver and gut bacteria immediately.

For this reason, L-citrulline might be better absorbed into your bloodstream than L-arginine.

As for nitrates, you can find these substances in certain foods, such as beets and green leafy vegetables.

This article will discuss what you should know about NO supplements—including their potential uses, side effects, interactions, and more.

Supplement Facts

• Active Ingredient(s) : Nitric oxide, L-arginine, L-citrulline, nitrates
• Alternate Names(s) : Nitric oxide, NO, nitric oxide supplements, nitric oxide boosters, Genosyl, Inomax, Noxivent
• Legal Status : Food, supplement, prescription medication
• Suggested Dose : May vary based on dosage form and medical condition
• Safety Considerations : Possible side effects, interactions, and special considerations for children, pregnancy, and breastfeeding

Dietary supplements are not regulated like drugs in the United States. They can cause interactions with medications or have other safety concerns.

For this reason, it’s important to be aware of what to look for when choosing a supplement , such as third-party testing, potential drug interactions, and more.

While more extensive research is necessary in regard to effectiveness, people use nitric oxide (NO) supplements for various health conditions.

Research is most robust for NO's effects concerning the following:

• Heart health
• High blood pressure in pregnancy
• Erectile dysfunction (ED)
• Athletic performance

Miniseries / Getty Images

Heart Health

NO supplements may contain substances—like the L-arginine amino acid. And your body may use and turn L-arginine into NO, which widens blood vessels and improves blood flow.

Due to these effects, NO supplements may support heart health. In fact, a systematic review and meta-analysis (analysis of a collection of studies) showed that L-arginine increased NO levels and blood flow in select groups of people, such as people with heart disease . These effects may also apply to people with excess weight , type 2 diabetes , or both.

These results may support L-arginine's effects on improving blood vessel function in people with heart disease risk. But it's unclear how effective NO supplements—like L-arginine—are because of variability (important differences) between the studies. For example, there were differences in dosage forms, dosages (amounts or strengths), and how long L-arginine worked.

Additional research with higher-quality clinical trials is warranted—especially due to a concern that L-arginine might cause more harm in people with a recent heart attack .

High Blood Pressure in Pregnancy

High blood pressure in pregnancy is a dangerous condition that may negatively affect the parent and unborn fetus.

In an older study, pregnant people had lower blood pressure with long-term use of NO supplements, such as L-arginine. However, conflicting evidence exists for this use.

More research with higher-quality clinical trials is necessary to provide additional data.

Erectile Dysfunction

A review suggested that L-arginine alone or in combination with other medications might help people with erectile dysfunction (ED). The review article also mentioned a study supporting the use of L-citrulline—another NO supplement—in people with mild ED.

But future research with higher-quality and larger studies is still necessary.

Athletic Performance

A review article looked at short-term use of NO supplements—particularly L-citrulline and nitrates. It showed some promise in relaxing blood vessels and improving blood flow to increase muscle performance, size, and strength.

As for L-arginine, there is little evidence to support its use in improving athletic performance.

The evidence for these NO supplements is mixed. However, L-citrulline and nitrates seemed to be the most promising because they are better absorbed into the bloodstream when compared to L-arginine.

But additional research is still warranted, especially longer-term studies.

In recent years, there has been a lot of progress toward understanding nitric oxide (NO) and its effects in the human body.

Although additional extensive clinical trials are still necessary, research within the past few decades have shown a possible relationship between NO deficiency and several medical conditions.

What Causes a Nitric Oxide Deficiency?

In general, NO levels might depend on the following:

• Diet : The typical Western diet isn't a rich source of nitrates and nitrites. But eating more fresh vegetables—like from the DASH (Dietary Approaches to Stop Hypertension) diet —will likely increase the amount of nitrates and nitrites in your diet. According to a 2012 review article, a diet with more nitrates lowered the blood pressure of healthy volunteers. But longer-term studies are still warranted.
• Physical inactivity : Physical inactivity may increase heart-related problems. And there is growing evidence that low NO levels might play a role in this. Exercise, on the other hand, may increase NO levels.
• Mitochondrial diseases : Mitochondrial diseases are a group of medical conditions that run through families. In general, these conditions affect your mitochondria. Mitochondria are small components (parts) within your cells that are responsible for making energy. People with mitochondrial diseases have cells that don't make enough energy. People with these conditions may also have low NO levels. This might be because the mitochondria are having trouble making L-citrulline that converts to L-arginine, which eventually turns into NO. People with these conditions may also tend to clear out arginine from the body at a higher rate when compared to the general population.
• Medications : There is a possible relationship between some medications and low NO levels. Examples of these medications include antibiotics (e.g., clindamycin), proton pump inhibitors (PPIs) such as Prilosec (omeprazole), and nonsteroidal anti-inflammatory drugs (NSAIDs) such as Advil or Motrin ( ibuprofen ) and Aleve (naproxen).

How Do I Know if I Have a Nitric Oxide Deficiency?

If you have a nitric oxide (NO) deficiency, you'll experience such short-term symptoms as blood vessel dysfunction and high blood pressure .

In general, a low NO level is likely an early sign that hints at an onset of a chronic (long-term) medical condition.

Long-term or worsening NO deficiency symptoms may include the following:

• Amputation from worsening diabetes (high blood sugar)
• Blindness from diabetes-related eye problems
• Heart disease
• Kidney disease
• Diabetic neuropathy (nerve pain)

What Are the Side Effects of Nitric Oxide?

Nitric oxide (NO) supplements, as with many medications and natural products, may have side effects.

Common Side Effects

Common side effects of NO supplements may include:

• Bloating (gas)
• Fast heartbeat
• Nausea and vomiting
• Stomach pain

Severe Side Effects

Severe side effects are possible, especially with large doses of magnesium. Examples of serious side effects include:

• Severe allergic reaction : A severe allergic reaction is a profound side effect possible with any medication or natural product. If you're having a severe allergic reaction , symptoms may include breathing difficulties, itchiness, and rash.
• Heart problems : If you already have a heart condition, NO supplements may worsen it. In particular, L-arginine in people with a recent heart attack might raise the risk of another heart attack, hospitalization (being admitted to the hospital), and death.
• Low blood pressure : NO supplements might lower your blood pressure. If your blood pressure is too low , you might experience dizziness and fainting spells.
• Lung problems : As an inhaled (breathed-in) prescription, nitric oxide's potentially severe side effects may generally include lung and breathing problems.
• Abnormal white blood cell (WBC) count : L-arginine may raise the levels of certain WBCs .

If you're having a severe allergic reaction or if any of your symptoms feel life-threatening, call 911 and get medical help right away.

A healthcare provider may advise against using nitric oxide (NO) supplements if any of the following applies to you:

• Severe allergic reaction : Avoid NO supplements if you have a known allergy to them or their ingredients or parts. If you're unsure if it's safe for you, ask a pharmacist, registered dietitian (RD) or registered dietitian nutritionist (RDN) , or healthcare provider for more information.
• Pregnancy : NO supplements may have the potential use for high blood pressure in pregnancy. But most NO supplement labels are unlikely to target pregnant people. Before taking NO supplements, contact a healthcare provider to discuss the benefits and risks.
• Breastfeeding : Nitric oxide and nitrates are normally present in breast milk. As an inhaled (breathed-in) prescription, using nitric oxide increases NO blood levels of breastfeeding parents—but not NO levels in breast milk. What's more, nitric oxide as an inhaled prescription has been used in newborns to treat respiratory failure, but NO supplements might be safe while breastfeeding. Before taking NO supplements, reach out to a healthcare provider to discuss the benefits and risks.
• Adults over 65 : Some older adults tend to be more sensitive to medication side effects, particularly those with a recent heart attack. So, use caution and speak with a healthcare provider before taking NO supplements.
• Children : As an inhaled prescription, nitric oxide has been used in children to treat respiratory failure. And there are a few NO supplements that target children. Since there is limited information about the effects and safety of NO supplements in children, however, talk about the benefits and risks of these supplements with a healthcare provider.
• Abnormal white blood cell (WBC) count : L-arginine may raise your WBC count. So, your healthcare provider may want to closely monitor you and your WBC levels—if you're taking L-arginine.
• Certain digestive system problems : Nitric oxide might play a role in balancing the amount of water and electrolytes (salts) in your intestines (gut). But if there is already an imbalance, you might have a higher likelihood of side effects from NO supplements. So, talk with a healthcare provider about benefits and risks before trying NO supplements.
• Guanidinoacetate methyltransferase deficiency (GAMT) : GAMT is a condition that runs in families. People with GAMT don't have a protein to convert arginine into creatine. Therefore, people with GAMT should avoid NO supplements—like arginine.
• Heart conditions : NO supplements may worsen your heart condition, especially a recent heart attack in older adults. So, healthcare providers are unlikely to recommend L-arginine if you have a recent heart attack.
• Low blood pressure : If you have low blood pressure , healthcare providers will likely recommend that you stop NO supplements before going into surgery.

Dosage: How Much Nitric Oxide Should I Take?

Always speak with a healthcare provider before taking a supplement to ensure that the supplement and dosage are appropriate for your individual needs.

Each NO supplement may contain different ingredients in different amounts.

Moreover, further, extensive research with higher-quality clinical trials is warranted to better understand the effects and safety of NO supplements.

For these reasons, there are no guidelines on the appropriate dosage to take NO supplements for any condition.

If you take NO supplements, follow a healthcare provider's suggestions and product label instructions.

Dietary supplements are not regulated like drugs in the United States, meaning the Food and Drug Administration (FDA) does not approve them for safety and effectiveness before products are marketed. Choose a supplement tested by a trusted third party, such as U.S. Pharmacopeia (USP), ConsumerLab.com, or NSF.org, whenever possible. However, even if supplements are third-party tested, they are not necessarily safe for all or effective in general. Therefore, talking to your healthcare provider about any supplements you plan to take and asking about potential interactions with other supplements or medications is important.

What Happens if I Take Too Much Nitric Oxide?

In general, L-arginine and L-citrulline are considered safe.

However, each nitric oxide (NO) supplement might contain different ingredients in various amounts.

So, it's impossible to know the overall safety of all NO supplements.

For this reason, more information about the safety, toxicity, and overdoses of individual NO supplements in humans is needed.

Symptoms of overdoses with NO supplements, however, are likely similar to its potential common and serious side effects—just excessive and more severe.

For example, high NO levels might result in lung injury and methemoglobinemia , which can be life-threatening.

In methemoglobinemia , your red blood cells (RBCs) are having trouble transporting oxygen throughout your body. Symptoms may include:

• Breathing problems

Nitric oxide (NO) supplements might interact with the following:

• Antibiotics : There is a possible relationship between antibiotics and low NO levels. For this reason, antibiotics might work against NO supplements.
• Blood pressure medications : NO supplements—like L-arginine—have lowered blood pressure. So, this may have additive effects with other blood pressure medications, such as Zestril (lisinopril) . If your blood pressure is too low , you might experience dizziness and fainting spells.
• Diabetes medications : NO supplements—like L-arginine—have lowered blood sugar. This might have additive effects on your diabetes medications, such as insulin . Symptoms of too-low blood sugar include tremors and sweating.
• Erectile dysfunction (ED) medications : NO supplements have been used for ED. In studies, nitric oxide supplements have lowered blood pressure, similar to several ED medications, such as Viagra (sildenafil). For this reason, taking these medications together might result in excessively low blood pressure. Check with your healthcare provider.
• Inhaled NO prescriptions : In general, the purpose of NO supplements is to increase NO levels. Inhaled NO prescriptions also increases NO levels. As a result, NO supplements might have additive effects with inhaled NO prescriptions. High NO levels may result in lung injury and methemoglobinemia , which can be life-threatening.
• NSAIDs : There is a potential relationship between NSAIDs and low NO levels. So, NSAIDs might work against NO supplements. Advil (ibuprofen) is an example of an NSAID.
• Proton pump inhibitors (PPIs) : PPIs—like Nexium (esomeprazole)—might lower NO levels. Therefore, PPIs may work against NO supplements.

It is essential to carefully read a supplement's ingredients list and nutrition facts panel to know which ingredients and how much of each ingredient is included. Please review this supplement label with your healthcare provider to discuss potential interactions with foods, other supplements, and medications.

In general, nitric oxide (NO) supplements—like L-arginine, L-citrulline, and nitrates—have potential uses for:

• Sexual health

Other potentially similar supplements include the following:

• Creatine : With creatine , you may notice an increase in strength, muscle mass, and endurance from vigorous exercise. But creatine also comes with side effects.
• Garlic : Garlic might have beneficial effects on blood pressure and cholesterol, which are risk factors for heart disease.
• Omega-3 fatty acids : Omega-3 fatty acids from fish oil may lower your blood pressure.
• Yohimbe : A potential use of yohimbe is erectile dysfunction (ED), but there is limited research to support this. In the United States, it's also illegal to market over-the-counter (OTC) yohimbe for ED without approval from the Food and Drug Administration (FDA).

Only combine multiple natural products after first talking with a healthcare provider, pharmacist, or dietitian. Checking in can help you avoid possible harmful interactions and side effects and ensure you're giving these supplements a fair trial at appropriate doses.

There are several food sources of nitric oxide. Nutrition guidelines typically emphasize food sources of nutrients to improve health.

Food sources of nutrients are preferable to supplements.

However, there is still a place for supplements for certain groups of people, such as those with certain medical conditions.

What Foods Contain Nitric Oxide?

Some foods are rich in nitrates and nitrites. And through your diet, your body may convert the nitrates and nitrites to nitric oxide.

Examples of foods that are good sources of nitrates or nitrites are:

In general, fresh and leafy green vegetables are good options.

Amino acids may also be found in food. For example, foods that contain L-arginine include:

• Dairy products

Nitric Oxide Supplements

Nitric oxide (NO) supplements don't actually have the nitric oxide gas.

Instead, NO supplements typically contain substances, such as amino acids—like L-arginine and L-citrulline—and nitrates. And your body may convert these substances into nitric oxide.

In general, NO supplements are likely commonly available as capsules. Other dosage forms of NO supplements include:

• Chewable gummies

But some of these other dosage forms might be in combination with other ingredients.

You may also see vegetarian and vegan options.

What is best for you will depend on form preference and what you hope to get in terms of effects.

Each product may work a bit differently, depending on the form.

Following a healthcare provider's recommendations or label directions is essential.

Other Ways to Increase Nitric Oxide

Aside from diet or supplements, exercise is another way to increase nitric oxide (NO) levels.

Nitric oxide (NO) supplements contain substances that your body may turn into NO, which is a naturally occurring gas that relaxes blood vessels and increases blood flow.

NO supplements have a few potential uses for:

Since more extensive research is needed, you must ensure the diagnosis and treatment of your medical conditions are completed on time.

Before using NO supplements, ask a registered dietitian, pharmacist, or healthcare provider to weigh in on the process of deciding what may benefit you.

Nitric oxide is a naturally occurring gas in your body.

In your body, nitric oxide can relax your blood vessels to increase blood flow.

Nitrite turns into nitric oxide in the body.

In general, you may increase nitric oxide with diet, supplements, or exercise.

To safely take supplements—like nitric oxide (NO) supplements—inform your healthcare providers and pharmacists about any and all medications you take. This includes over-the-counter (OTC), herbal, natural medicines, and supplements. They can help prevent possible interactions and side effects. They can also ensure that you’re giving NO supplements a fair trial at appropriate doses.

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By Ross Phan, PharmD, BCACP, BCGP, BCPS Ross is a writer for Verywell with years of experience practicing pharmacy in various settings. She is also a board-certified clinical pharmacist and the founder of Off Script Consults.

NITRIC OXIDE

Sep 16, 2014

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NITRIC OXIDE. Aseem Hussain. NITRIC OXIDE. Nitric oxide is a gas. It is highly reactive; and is one of the products in automobile exhaust and plays a major role in atmospheric pollution. Surprisingly, it was found that it has important physiological functions. NITRIC OXIDE.

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NITRIC OXIDE Aseem Hussain

NITRIC OXIDE • Nitric oxide is a gas. It is highly reactive; and is one of the products in automobile exhaust and plays a major role in atmospheric pollution. • Surprisingly, it was found that it has important physiological functions.

NITRIC OXIDE • This was the first discovery that a gas can act as a signal molecule in the organism. • A highly reactive compound, it only exists for six to ten seconds inside the body, then it is converted, by oxygen, into other compounds of nitrogen called nitrites. • Uniquely, it is one of the few compounds with an odd number of electrons thereby making it a ‘free-radical' prone to ionizations.

NITRIC OXIDE • NO is synthesized within cells by an enzyme NO synthase (NOS).

Sub-types of NOS • nNOS : found in neurons • iNOS : is inducible and found in macrophages. Whereas the levels of nNOS and eNOS are relatively steady, expression of iNOS genes awaits an appropriate stimulus (e.g., ingestion of a parasite). • eNOS : found in the endothelial cells that line the lumen of blood vessels.

NITRIC OXIDE • All types of NOS produce NO from arginine with the aid of molecular oxygen and NADPH.

NITRIC OXIDE • NO diffuses freely across cell membranes. • There are so many other molecules with which it can interact, that it is quickly consumed close to where it is synthesized. • Thus NO affects only cells near its point of synthesis.

NITRIC OXIDE FUNCTIONS • Blood Flow • NO relaxes the smooth muscle in the walls of the arterioles. • Mice whose genes for the NO synthase found in endothelial cells (eNOS) has been “knocked out" suffer from hypertension. • Nitroglycerine, which is often prescribed to reduce the pain of angina, does so by generating nitric oxide, which relaxes the walls of the coronary arteries and arterioles.

Platelet aggregation • NO also inhibits the aggregation of platelets and thus keeps inappropriate clotting from interfering with blood flow

Kidney Function • Release of NO around the glomeruli of the kidneys increases blood flow through them thus increasing the rate of filtration and urine formation.

Other functions • Penile Erection • Intestinal peristalsis • Contractility of the smooth muscle wall of the uterus during labor • NO stimulates secretion from several endocrine glands. • Neurotransmitter • Memory and learning.

NITRIC OXIDE • NO aids in the killing of engulfed pathogens like bacteria within the lysosomes of macrophages • Harmless bacteria, living as commensals at the rear of our throat, convert nitrates in our food into nitrites. When these reach the stomach, the acidic gastric juice (pH ~1.4) generates NO from them. This NO kills almost all the bacteria that have been swallowed in our food.

Mechanisms of NO Action • The signaling functions of NO begin with its binding to protein receptors on or in the cell. The binding sites can be either: • a metal ion in the protein or • one of its Sulfur atoms e.g., on cysteine. • In either case, binding triggers a change in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein target for NO seems to be guanylyl cyclase, the enzyme that generates the second messenger cyclic GMP (cGMP).

NITRIC OXIDE • The discovery of the biological functions of nitric oxide in the 1980s came as a complete surprise Nitric oxide was named "Molecule of the Year" in 1992 by the journal Science, • a Nitric Oxide Society was founded, and a scientific journal devoted entirely to nitric oxide was created. • The Nobel prize in Medicine in 1998 was awarded for the discovery of the signaling properties of nitric oxide.

NITRIC OXIDE • It is estimated that yearly about 3,000 scientific articles about the biological roles of nitric oxide are published. • The following article is one of these…

Nitric oxide-induced cellular stress and p53 activation in chronic inflammation • This article was published in “The Proceedings of the National Academy of Sciences of United States of America” on January 7, 2003.

Introduction: NO as a free radical • Free radicals perform beneficial tasks such as aiding in the destruction of microorganisms and cancer cells. • Excessive production of free radicals however can lead to damage of cellular structure and enzymes.

Introduction • Inflammation is the body's response to injury • The inflammatory response includes redness, swelling and an increased local supply of white blood cells. These changes are an attempt to ward off infections and to help repair damaged tissue.

however, the inflammatory response may be excessive and result in untoward consequences like cancer and worsening of the disease.

An increased cancer risk occurs in tissues with chronic inflammation • There are multiple free radicals generated by chronic inflammation and they target various genes and proteins to cause cancer

In this article, NO and its actions on p53 tumor suppressor gene and how this results in cancer is studied.

p53 tumor suppressor gene • The product of the tumor suppressor gene p53 (chromosome 17) is a protein that prevents a cell from completing the cell cycle if • its DNA is damaged or • the cell has suffered other types of damage. • If the damage is minor, p53 halts the cell cycle — hence cell division — until the damage is repaired or • if the damage is major and cannot be repaired, p53 triggers the cell to commit suicide by apoptosis.

p53 tumor suppressor gene • These functions make p53 a key player in protecting us against cancer; that is, an important tumor suppressor gene.

There is increased p53 mutation in inflamed colon tissue from patients with ulcerative colitis, a cancer-prone inflammatory bowel disease, along with elevated nitric oxide synthase (iNOS) levels • The mutated p53 cannot bind to its transport protein and accumulates in cells

p53 mutations result in genomic instability because of diminished regulation of cell cycle checkpoints, DNA repair, and apoptosis. • In this article, several mechanisms are explained through which NO induces p53 mutation in vitro and in • cells exposed to NO-generating drugs and NO-releasing macrophages and • Ulcerative colitis.

Methods used in this study • Comet assay • Cell culture • Co-culture • Immunoprecipitation • Western Blot analysis • Mitotic index assays • Immunohistochemistry • Nitrate and nitrite assay

Methods • Comet Assay • the Comet assay is a simple, rapid and sensitive technique for analyzing and quantifying DNA damage in individual cells.

Comet Assay • Cells are embedded in a thin agarose gel on a microscope slide. • The cells are lysed to remove all cellular proteins and the DNA subsequently allowed unwinding under alkaline/neutral conditions. Following unwinding the DNA is electrophoresed and DNA stained with a fluorescent dye. • During electrophoresis, broken DNA fragments (damaged DNA) or relaxed chromatin migrates away from the nucleus. • The extent of DNA liberated from the head of the comet was directly proportional to the DNA damage.

Mitotic index • The percentage of cells actively dividing are calculated

Cell culture • The important cell lines used were • The MCF-7 human cancer cell line • macrophage cell line, ANA-1 • colon carcinoma cells (HCT)

Nitrate and nitrite assay • Nitrite and nitrate are the stabile end products of NO metabolism and were measured in culture media with a fluorometric assay kit.

Hypothesis • First, to identify whether NO damages p53, MCF-7 cells (human cancer cell line containing p53) were exposed to NO donors S-nitrosoglutathione or spermine NONOate . • These chemicals result in NO induced DNA damage by p53 phosphorylation (serines 15, 20, 33, 46, 315, and 392), and acetylation (lysine 382), leading to p53 mutation and accumulation

Figure 1a • DNA damage is induced in MCF-7 cells after exposure to 0.5 mM SPER/NO. Cells were exposed for 4 h, then processed for the alkaline comet assay.

Figure 1b • Section ‘b’ and ‘c’ are western blots • Increase in p53 posttranslational modifications and p53 levels after exposure to 0.5 mM SPER/NO recorded by Western blot assays. were performed. • UV treatment (known to cause maximal damage) was used as a positive control.

Figure 1c • Next, MCF-7 cells were co-cultures with NO releasing macrophages and the abnormal p53 accumulation and phosphorylation of p53 was noted using western blot analysis. • After 8 h of coincubation, cells were lysed, and Western blot assays were performed.

Lane 1, MCF-7 cells only • lane 2, MCF-7 cells + unstimulated macrophages • lane 3, MCF-7 cells + stimulated macrophages • lane 4, unstimulated macrophages only • lane 5, stimulated macrophages only • lane 6, MCF-7 cells + cytokine stimulation • lane 7, MCF-7 cells + cytokine stimulation + L-NMMA • lane 8, MCF-7 cells + stimulated macrophages  + L-NMMA • lane 9, HCT 116 p53 / cells • lane 10, MCF-7 cells + UV.

p53 protein was isolated by using double immunoprecipitation with mouse monoclonal anti-p53 antibodies

Antibodies used in western blot • The following primary antibodies were used for protein analysis by Western blotting procedures: • anti-human p53 phosphoserine 15 antibody • acetylated lysine 382 antibody • Other antibodies used were anti-human p21antibodies, anti-human iNOS antibodies

NO-Induced Phosphorylation of p53 at Serine 15 • The serine 15 phosphorylation on p53 is a principal residue modified in vitro. This modification mediates p53 accumulation and activation. • The investigators focused on this residue. • Cell lines with and without p53 were exposed to NO donors and Phosphorylation of p53 at serine 15 was studied. It was noted that when compared to ‘knockouts’, p53 phosphorylation at 15 was increased when the cell lines were exposed to nitric oxide donors • Thus serine 15 p53 phosphorylation is an important step in carcinogenesis.

NO-Induced p53 Phosphorylation Activates p53 Targets and Engages a G2/M Checkpoint. • This was intended to show that NO also has some protective effects in preventing cancer • NO reduces the number of cells that are actively dividing by causing a shift in cell cycle

at G1 checkpoint, an early decrease in the percentage of cells in active S-phase, and • at G2/M checkpoint

Changes in cell cycle by NO • HCT 116 (colon carcinoma cells) with p53 and HCT 116 without p53 cells were exposed to the 0.5 mM SPER/NO for indicated time points (hr), then lysed. Western blot assays were performed.

There is a p53- and p21-dependent G2/M arrest in colon cancer cells exposed to NO. • Thus, NO caused a shift in cell cycle by preventing active cell division, increasing cells in G2 phase and decreases mitotic index

p53 Is Phosphorylated, Accumulates, and Is Active in ulcerative colitis, a Chronic Inflammatory Disease. • Ulcerative colitis is a chronic inflammatory condition of the colon and it can eventually lead to colon cancer • In this study tissue samples from both normal colons and colons with ulcerative colons were obtained. • The investigators wanted to prove that there is increased NO production and hence increased mutation and accumulation of p53 in ulcerative colitis

Ulcerative colitis • Nine of eleven UC cases had detectable levels of nitric oxide synthase (iNOS) protein. In contrast, nitric oxide synthase levels were undetectable in normal colon tissues from non-UC donors. • significant increase (P < 0.05) in nitric oxide synthase levels with increasing degree of inflammation was noted.

Ulcerative colitis • p53 protein levels and posttranslational modifications also were undetectable in normal colon tissues • In contrast, 9 of 11 UC patients had detectable P-Ser-15 levels, and all 11 UC patients had detectable p53. There also was a significant increase in P-Ser-15 levels (P < 0.05) with increasing degree of inflammation.

Ulcerative colitis • There is a immediate rise in P-Ser-15 levels with minimal inflammation and this finding is consistent with the hypothesis that P-Ser-15 is a sensitive biomarker of inflammation. • There also were detectable levels of acetylated lysine 382 

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Nitric oxide: a new role in intensive care

Alexandra lee.

1 Ulster Hospital, Dundonald, Belfast, Northern Ireland.

Warwick Butt

2 Department of Intensive Care, Royal Children's Hospital, Melbourne, VIC, Australia.

3 Murdoch Children's Research Institute, Melbourne, VIC, Australia.

4 Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

Inhaled nitric oxide has been used for 30 years to improve oxygenation and decrease pulmonary vascular resistance. In the past 15 years, there has been increased understanding of the role of endogenous nitric oxide on cell surface receptors, mitochondria, and intracellular processes involving calcium and superoxide radicals. This has led to several animal and human experiments revealing a potential role for administered nitric oxide or nitric oxide donors in patients with systemic inflammatory response syndrome or ischaemia-reperfusion injury, and in patients for whom exposure of blood to artificial surfaces has occurred.

Nitric oxide (NO) is a free radical 1 that acts as a signalling molecule, modulating functions across multiple body systems. 2 Endogenous NO is released by blood vessel endothelium in response to stimulation from the autonomic nervous system, shearing forces generated by increased blood flow, and a variety of ligands that act on endothelial cell surface receptors. Endothelial cell-derived NO inhibits platelet aggregation, inhibits white blood cell activation, and works directly on vascular smooth muscle to cause vasodilation 3 and alter regional blood flow. NO also affects cell wall permeability, cellular pumps that control entry of calcium into cells, and mitochondrial permeability transition pore (mPTP) receptors that affect access of superoxide radicals into mitochondria.

In cardiac myocytes, NO increases contractility and also increases heart rate. 4 Myocardial oxygen consumption is also reduced by endogenous basal NO, shown by an increased oxygen requirement after administration of a nitrogen oxide synthase inhibitor in patients, which is thought to be due to more efficient myocardial contractility. 5 Furthermore, NO is thought to improve myocardial distensibility; patients with higher levels of nitric oxide synthase gene expression have been shown to have less stiff left ventricles, and therefore a higher preload reserve that preserves stroke volume. 6 It has also been shown that NO synthesis and release is impaired in states of systemic inflammation associated with cardiopulmonary bypass (CPB). 7 In the same conditions, levels of NO inhibitor molecules are also raised. 8

Despite an increase in case complexity, survival after paediatric and neonatal cardiac surgery continues to improve, 9 , 10 so there is an increasing focus on reducing long term morbidity. Globally, the incidence of congenital heart disease is estimated to be 1 in 100 live births. 11 In about half of cases, surgical intervention will be required, 12 and CPB is used in most of these cases. CPB provides cardiac and respiratory support via an extracorporeal system, 13 which creates a bloodless and non-pulsatile surgical field. A routine consequence of the procedure is systemic inflammation and ischaemia-reperfusion injury (IRi), due to blood contact with foreign surfaces, which causes injury to the heart, kidneys, brain and other organs. More recently, it has also been recognised that stored red blood cells rapidly develop a defect that limits oxygen delivery. NO also reverses the red cell storage defect.

For these reasons, exogenous NO may have a new role in any clinical scenario that includes systemic inflammatory response syndrome (SIRS) or IRi; this includes cardiac arrest, myocardial and cerebral ischaemia, sepsis, cardiac surgery and extracorporeal membrane oxygenation (ECMO). Some animal and human data from these scenarios have been published. Most human clinical data comes from patients who have undergone paediatric cardiac surgery, and we present these data in this review, along with a small amount of data from patients who have undergone ECMO.

Eligibility criteria

This review includes human data from adult and paediatric patients who underwent CPB and suffered IRi as a direct consequence of CPB, plus data from animal studies including IRi. Studies must have included exposure to exogenous NO during CPB or the peri-ischaemic period, and must have included a comparison with controls where NO was not administered. Outcomes examined encompass endorgan effects or biological markers. Pulmonary outcomes (eg, improved gas exchange or pulmonary hypertension) were excluded from this review as the effects of NO on pulmonary outcomes are already well known. Study designs that were considered eligible included randomised control trials, cohort studies and case–control studies; conference abstracts describing small case series were excluded.

Search strategy

Electronic searches of MEDLINE, Scopus and EMBASE were conducted in May 2018, and updated in August 2019. A predefined search strategy was developed for MEDLINE using Medical Subject Headings (MeSH) terms and keywords and operating theatre/room to capture relevant citations. In addition, references were reviewed to identify potentially relevant papers missed by the searches. Results were limited to articles written in English but no date restrictions were applied. Separate databases of human and animal studies were constructed in Endnote (Clarivate Analytics, Philadelphia, PA, US) with duplicates removed. The results were reviewed, and full text articles were selected based on predefined criteria. If eligibility was unclear, the full text article was retrieved. Articles were reviewed and results were synthesised qualitatively.

A total of 1267 studies relating to NO use in animal models were initially identified, and these were narrowed down to seven by screening titles and abstracts and reviewing full text articles. A total of 499 studies of trials in humans were retrieved from the electronic search, of which four were included in the final review that followed screening of the results. One study on the safety of NO in patients receiving ECMO was also included. The human studies were categorised based on the patient population: adult (n = 3) or paediatric (n = 2). All five studies were prospective randomised trials, and blinding was used in three.

Review of animal studies

Experimental work in murine models of myocardial ischaemia–reperfusion injury has demonstrated a promising effect of NO on myocardial infarct (MI) size and function, and is summarised in Table 1 . Hataishi and colleagues supplemented the ventilator with NO for 20 minutes before reperfusion following ligation of the left anterior descending coronary artery. 18 Twenty-four hours after surgery, animals in the intervention group had markedly better systolic function compared with untreated animals, based on echocardiogram findings. Also, heart slices were obtained and stained so that infarct size could be measured via fluorescence microscopy. In animals inhaling 80 ppm NO, the ratio of MI area to left ventricular area after 30 minutes of ischaemia decreased (64 ± 3% on air v 58 ± 5% on NO) and the ratio of MI area to area without microspheres after 30 minutes of ischaemia decreased(20 ± 3% on air v 9 ± 1 % on NO). These findings were replicated when the duration of ischaemia was increased. In addition, NO was associated with reduced myocardial neutrophil infiltration. 18

Summary of animal studies relating to use of nitric oxide (NO) in ischaemia-reperfusion injury

AAR = area of myocardial tissue at risk; CPR = cardiopulmonary resuscitation; GFAP = glial fibrillary acidic protein.

Results of further studies, using the same murine model, concur with these results. Nagasaka and colleagues showed a reduction in markers of myocardial injury in mice that inhaled NO before reperfusion, and a 32% decrease in size of MI when NO was inhaled for an hour before reperfusion (P ≤ 0.05). 19 It should be noted that in these studies, NO was only administered during periods of ischaemia, meaning that NO metabolites did not enter ischaemic tissue until reperfusion had occurred. In a similarly designed study, Neye and colleagues also compared NO administration during the reperfusion; they found that NO inhalation that commenced during reperfusion produced non-significant effects, but continuous inhalation throughout ischaemia and reperfusion was associated with the greatest reduction in myocardial area at risk. 17

Results of several studies indicate that NO may also confer protection against ischaemic injury in neuronal tissue. Although cerebral blood flow is not altered by NO in normal physiological conditions, there is evidence that NO has a vasodilatory effect in experimental models of cerebral ischemia. Terpolilli and colleagues subjected mice to 45 minutes of ischaemia, through occlusion of the middle cerebral artery, and then stained coronal brain slices with cresyl violet to highlight infarcted tissue. 20 Commencing with 50 ppm NO inhalation during ischaemia resulted in reduced ischaemic tissue injury as compared with the control group (no NO inhalation). In a similar trial, Li and colleagues observed a reduced infarct volume 24 hours after cerebral artery ischaemia, but only at 10 ppm NO; at higher NO concentrations, infarct volume was reduced up to 16 hours but no significant effect was observed at 24 hours. 15 Contrary to this, Kida and colleagues noted no increase in cerebral blood flow with NO, 16 indicating no significant vasodilatory effect but possible beneficial results owing to reduced water diffusion abnormality and cytokine induction. 14 , 16 Age- and weight-matched male C57BL/6J wild-type, sGCα1-deficient and NOS3-deficient mice were subjected to 7.5 minutes of potassium chloride-induced cardiac arrest followed by cardiopulmonary resuscitation and inhalation of air supplemented with NO for 23 hours. 14 The NO intervention group had higher 10-day survival rates than the control group (11/13 mice v 4/13 mice; P = 0.003) and higher neurological function scores 96 hours after induced ischaemia. Magnetic resonance imaging conducted at 24 hours showed areas of hyperintense diffusion-weighted imaging in the control group, a measure of cerebral oedema, while this was largely absent in the intervention group. In addition, statistical analysis showed average apparent diffusion coefficients that were universally lower in the NO group (P ≤ 0.05). Furthermore, the induction of genes encoding inflammatory cytokines tumour necrosis factor-α, NADPH oxidase 2 (NOX2), interleukin-6 and interleukin-1β was prevented in wild-type mice subjected to NO inhalation. 14

Review of human studies

Adult patients.

Studies that have translated this animal research to human patients are summarised in Table 2 . A small non-blinded study was conducted by Kamenshchikov and colleagues, 21 with 29 patients undergoing aortic valve replacement and aortocoronary bypass randomly assigned to receive 500 ppm NO through the ventilator circuit before transferring to delivery via the CPB pump prime solution. Surrogate biochemical markers of myocardial injury were measured, and each revealed a higher level of injury in the control group: creatinine kinase–muscle/brain (CK-MB) levels were significantly lower at 24 hours (P = 0.01) and 48 hours (P = 0.01) in the intervention arm, while cardiac troponin I (cTnl) levels ( P = 0.04) and B-type natriuretic peptide (BNP) levels (249 ± 71 pg/mL v 311 ± 141 pg/mL; P = 0.02) also showed blunted responses. Results of this study are positive but limited in terms of generalisability owing to the small number of participants and short follow-up period.

Summary of human studies relating to nitric oxide (NO) use in adult and paediatric patients who underwent cardiopulmonary bypass (CPB) and suffered ischaemia-reperfusion injury and systemic inflammatory response syndrome as a direct consequence of CPB

BNP = B-type natriuretic peptide; CK-MB = creatinine kinase–muscle/brain; cTnI = cardiac troponin I; ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; LCOS = low cardiac output syndrome; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NSAID = non-steroidal anti-inflammatory drug.

Similarly, Kamenshchikov and colleagues measured CK-MB and cTnl levels as proxy markers for myocardial necrosis after ischaemia induced by CPB. 22 Thirty patients undergoing elective primary coronary artery bypass grafting inhaled NO via the CPB circuit during the perioperative period. Twenty-four hours after surgery, decreased cTnl levels (1.79 ± 0.39 ng/mL v 2.41 ± 0.55 ng/mL; P = 0.001) and CK-MB levels (47.69 ± 8.08 U/L v 62.25 ± 9.78 U/L; P = 0.001) were seen relative to the control groups, indicating a lesser extent of myocardial injury. This study is also of limited generalisability owing to small sample size and lack of long term follow-up. However, combining these results with those of Gianetti et al adds weight to the plausibility of NO having a cardioprotective effect. 21 , 22

It has also been reported that the incidence of acute kidney injury (AKI) following CPB is lowered by concurrent NO administration. 23 A total of 244 adults with previously normal kidney function who were undergoing elective multiple valve replacement surgery with CPB were recruited into a double-blind randomised trial. Of them, 117 received 80 ppm NO and had a relative risk (RR) of AKI of 0.78 (95% Cl, 0.62–0.99; P = 0.014). Intrahospital mortality (RR, 0.31 [95% CI, 0.07–1.46]; P = 0.068) and 1-year mortality (RR, 0.41 [95% CI, 0.11–1.50]; P = 0.088) were both decreased in the NO group as compared with controls. There was no difference in the length of ICU stay between the groups.

Paediatric patients

Only two studies to date have been conducted in paediatric populations. A cardioprotective effect was observed by Checchia and colleagues in a population of 16 children undergoing tetralogy of Fallot repair who were recruited to the randomised, blinded, placebo-controlled study. 24 In this study, 20 ppm of gaseous NO was added to the CPB circuit oxygenator in the intervention group, while the control group received placebo gas treatment. Twenty-four hours after surgery, children receiving NO had lower cTnI levels (8.9 ± 2.6 ng/mL v 12.5 ± 2.7 ng/mL; P ≤ 0.05) and lower BNP levels (425 ± 154 pg/dL v 938 ± 511 pg/dL; P ≤ 0.05), indicating an apparent cardioprotective effect. The study also analysed the inflammatory response following CPB, with no significant differences in levels of serum interleukin-6, interleukin-9 or tumour necrosis factor-α between groups. Contrary to this, levels of P selectin, which is released by endothelial cells in response to inflammatory cytokines, were markedly reduced following reperfusion in the adult NO patients studied by Gianetti et al ( P = 0.02), 21 indicating a dampening of the inflammatory response.

James and colleagues examined low cardiac output syndrome (LCOS) as a specific primary endpoint, defined as lactate greater than 4 mmol/L and central venous oxygen saturation below 60%, or vasoactive inotrope score 10 or over or ECMO requirement. 25 In this study, the largest such trial conducted to date, 198 children who underwent any form of cardiac surgery with CPB were enrolled; 97 of them did not receive NO, and the remaining 101 children were randomly assigned to the NO intervention arm. The proportion of children developing LCOS was substantially lower in the intervention group (15% v 31%; P = 0.007); ECMO was used in one child in the treatment group, compared with eight in the control group. The results also showed a correlation between degree of benefit and age: the proportions of children < 6 weeks old developing LCOS in were 20% and 52%, respectively ( P = 0.012), but no significant difference was seen for children aged more than 2 years (19% v 21%, respectively; P = 0.901). This difference may be explained by an increased susceptibility to LCOS in neonates owing to a reduced cardiac reserve, a more severe inflammatory reaction to CPB and immaturity leading to increased risk of end-organ damage, 27 compared with older children following cardiac surgery. 28 , 29

Results from the study by Checchia et al indicated that although there was no difference in duration of hospital stay, there were significant reductions in time spent on mechanical ventilation (8.4 ± 7.6 v 16.3 ± 6.5 hours; P ≤ 0.05) and time spent in the cardiac intensive care unit (53.8 ± 19.7 v 79.4 ± 37.7 hours; P ≤ 0.05). 24 However, the larger trial by James et al found no differences in duration of ventilation (20.0 [range, 10–63] hours v 24.0 [range, 12–89] hours; P = 0.12), ICU length of stay (48.0 [range, 24–105] hours v 72.0 [range, 26–144] hours; P = 0.11) or hospital length of stay (9.0 [range, 6–17] days v 12.0 [range, 6–20] days; P = 0.164). 25 This difference could be a result of differences in baseline characteristics between the studies; for example, only surgery for a single indication (tetralogy of Fallot) was included in the study by Checcia et al while the study by James et al included all children undergoing any form of cardiac surgery with CPB. 24 , 25

Chiletti and colleagues describe their experience of 30 consecutive children supported with ECMO and receiving 20 ppm NO in the oxygenator of the ECMO circuit (which is similar to a CPB circuit). 26 Administration of NO into the ECMO circuit was not associated with methemoglobin rises nor was it associated with bleeding. In a follow-up poster from the same group, Pan et al 30 reviewed 334 ECMO runs from 2012 to 2018, 141 (41%) were after the introduction of routine circuit NO delivery. NO use was associated with a statistically significant reduction in the need for circuit changes (odds ratio [OR], 0.35 [95% CI, 0.16–0.77]; P = 0.009), but no changes in the incidence of neurological injury or hospital survival. However, in children aged 6 months or less (221/344, 64%), NO use was associated with less circuit changes (OR, 0.25 [95% CI, 0.09–0.71]; P = 0.009), less neurological injury (OR, 0.39 [95% CI, 0.16–0.96]; P = 0.04) and the same hospital survival rate (OR, 1.04 [95% CI, 0.54–1.99]; P = 0.91).

This review highlights possible new uses of NO either inhaled through the lungs or delivered in the fresh gas flow of the oxygenator of a CPB or ECMO circuit. In children, NO delivery during CPB is associated with reduced levels of serum inflammatory markers and decreased incidence of LCOS. In adults, a reduced inflammatory response is also seen, and the likelihood of developing AKI after CPB is reduced. These clinical findings are consistent with results from both human trials using surrogate biochemical markers, to quantify organ injury, and evidence from animal models of ischaemia–reperfusion injury. For example, NO appears to convey neuroprotective and cardioprotective effects in mice. These results make the potential benefits in humans plausible. Previous studies have proposed roles for NO in preventing platelet aggregation, impact on white cell migration and function and also providing anti-inflammatory effects 3 which may also provide protection against SIRS, ischaemia–reperfusion injury and infarction.

The strength of this review is the rigor of the methods used — the search strategy was as inclusive as possible, and references were reviewed to ensure capture of all relevant articles. A limitation is the small number of relevant human clinical trials conducted to date. Nonetheless, these initial results show improved clinical outcomes with the use of NO, particularly in paediatric patients after CPB.

Most of the outcomes discussed in this review were based on surrogate markers that assess end-organ function, as opposed to clinical outcomes. While these results are promising, the full extent of the effect of NO remains unclear, so further clinical trials are needed.

Currently, it appears that NO is safe and could mitigate IRi and SIRS in patients after CPB and children receiving mechanical support. Its antiplatelet effect could lead to increased circuit survival time and its potential benefits in brain injury and hypoxia ischaemia may lead to improved neurological outcomes.

Two large scale randomised trials looking at NO after CPB in children will compare NO to placebo, providing data on the effect of NO on LCOS, morbidity and mortality in children undergoing surgery for congenital heart defects. 31 Further work is also needed to examine the mechanism of action, serum NO concentrations and titration of treatment, and the timing of administration; such work will provide a full safety profile and optimise the use of this drug.

Nitric oxide administered to patients undergoing CPB appears to have several clinical benefits, including lower incidence of LCOS in infants and lower incidence of renal injury in adults. Further trials in different clinical situations involving SIRS, ischaemia–reperfusion, cardiac arrest and ECMO in cardiac surgery in both adults and children are ongoing.

Competing interests

Alexandra Lee was funded by the Stuart Green Memorial Trust and Sands Cox Society, but there was no funding for this article. The authors and researchers who assisted in developing this article had full access to all the data used (including statistical reports and tables), and can take responsibility for the integrity of the data and the accuracy of the data analysis.

• MyU : For Students, Faculty, and Staff

Dr. John R. Lockemeyer seminar

Dr. John R. Lockemeyer, Shell's Chief Scientist Catalysis, will deliver a department seminar, “The Shell Ethylene Oxide Technology Journey” on Tuesday, April 2nd at 1:25 p.m. in room B75 Amundson Hall.  Abstract: This presentation will offer an overview of some of the significant contributions by  Shell scientists, engineers, and technical staff to the field of ethylene oxide (EO)  production. Starting with Shell’s involvement in silver based EO catalysts dating  back to the 1930’s and culminating in the deployment of our most recent  achievement in the High Performance EO Process, the journey through the  approximately 90 inventive years will be described. This will include the major  advances in catalyst and process development, as well as some aspects of the  collaborative fundamental research pursued over the years.  Bio:  John was appointed Shell Chief Scientist for Catalysis in 2020 to provide technical leadership and  advise on strategy in areas involving catalysis and related fields. Passionate about inventions that help solve the world’s chemical and energy challenges, John  enjoys collaborating globally with scientists in Shell and at universities and technical organizations  on projects ranging from fundamental R&D to world scale deployment. Since joining Shell in  1989 his career has focused on catalyst development programs including hydrocracking, olefin  epoxidation, acetoxylation, Fischer-Tropsch, and a variety of other systems at locations in USA, Europe, and India. He is the recipient of the 2018 Southwest Catalysis Society Award for  Excellence in Applied Catalysis and is a listed inventor on 36 issued US Patents, 35 issued  European Patents, and numerous patents in international jurisdictions. John’s academic career started with a B.S. in Chemistry at Villanova University (1982), a Ph.D.  in Inorganic Chemistry at the University of Delaware (1987), and was capped by a postdoctoral  appointment at the University of Illinois at Urbana Champaign (1987-‘89). In 2010 he served as  the elected Chair of the Gordon Conference on Inorganic Chemistry.  

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