Nitric oxide (NO) is a colorless, odorless gas molecule that plays a crucial role in various physiological processes within the human body. It was first discovered in the 18th century, but its significance in biological systems wasn’t fully understood until the late 20th century.

In the body, NO acts as a signaling molecule, participating in the regulation of numerous functions, including vasodilation (the widening of blood vessels), neurotransmission, immune response, and the regulation of inflammation. One of its most notable roles is in the regulation of blood pressure, where it helps to relax and widen blood vessels, thereby improving blood flow.

What is nitric oxide?

Nitric oxide (NO) is a molecule composed of one nitrogen atom and one oxygen atom. It is a colorless and odorless gas at room temperature. It is a crucial signaling molecule in the body involved in various physiological processes.

One of its primary roles is as a vasodilator, meaning it relaxes and widens blood vessels, leading to increased blood flow. This function is vital for regulating blood pressure and delivering oxygen and nutrients to tissues throughout the body.

Nitric oxide also acts as a neurotransmitter. Additionally, it plays a role in the immune system, helping to combat pathogens and regulate inflammation.

Synthesis

NO is synthesized in the body through a process involving the conversion of the amino acid arginine into nitric oxide and citrulline. This synthesis is catalyzed by a family of enzymes called nitric oxide synthases (NOS).

There are three isoforms of nitric oxide synthase:

• Endothelial NOS (eNOS): Found primarily in endothelial cells lining blood vessels, eNOS produces nitric oxide in response to various physiological stimuli, such as shear stress and certain hormones.
• Neuronal NOS (nNOS or NOS1): Present in neurons of the central and peripheral nervous systems, nNOS is involved in neurotransmission and neuromodulation, synthesizing nitric oxide in response to calcium influx during neuronal activation.
• Inducible NOS (iNOS or NOS2): Induced in response to inflammatory stimuli, such as cytokines and bacterial endotoxins, iNOS produces large amounts of NO for immune defense mechanisms and inflammation regulation.

The synthesis of nitric oxide by nitric oxide synthases involves several steps:

• L-arginine binding: The enzyme binds the substrate L-arginine, along with other cofactors such as tetrahydrobiopterin (BH4) and oxygen (O2).
• Conversion to L-citrulline and nitric oxide: Through a series of enzymatic reactions involving the cofactors and molecular oxygen, nitric oxide synthase catalyzes the conversion of L-arginine into nitric oxide and L-citrulline.
• Release of nitric oxide: Once synthesized, NO is released from the enzyme and diffuses freely across cell membranes to exert its physiological effects.

Functions

NO is a versatile molecule with numerous functions in the human body. Some of its key functions include:

• Vasodilation: NO acts as a potent vasodilator, meaning it relaxes and widens blood vessels. This helps to improve blood flow and regulate blood pressure.
• Neurotransmission: Serves as a signaling molecule in the nervous system, facilitating communication between nerve cells (neurons). It plays a role in neurotransmission, synaptic plasticity, and other neurological processes.
• Immune response: It is involved in the immune system’s defense against pathogens. It helps to regulate inflammation and can be produced by immune cells to kill invading bacteria, viruses, and parasites.
• Regulation of platelet function: Helps to regulate platelet aggregation, which is important for preventing excessive blood clotting and maintaining cardiovascular health.
• Smooth muscle relaxation: It relaxes smooth muscles found in various organs and tissues, including the gastrointestinal tract, airways, and urinary bladder. This relaxation helps to regulate processes such as digestion, breathing, and urination.
• Angiogenesis: It plays a role in angiogenesis, the formation of new blood vessels from existing ones. This process is important for tissue repair, wound healing, and the growth of tumors.
• Penile erection: It  is a key mediator of penile erection. It stimulates the relaxation of smooth muscle cells in the erectile tissue of the penis, leading to increased blood flow and the attainment of an erection.
• Regulation of mitochondrial function: It can modulate mitochondrial respiration and energy production within cells, influencing cellular metabolism and overall energy balance.
• Regulation of gene expression: It can also act as a signaling molecule within cells to regulate gene expression and various cellular processes, including cell proliferation, differentiation, and apoptosis (programmed cell death).

NO rich foods

There are several foods that are naturally rich in nitrates, which can be converted into NO in the body. These foods include:

• Leafy greens: Spinach, kale, arugula, and other leafy greens are high in nitrates.
• Celery: Celery is another vegetable that contains nitrates and can contribute to nitric oxide production.
• Garlic: Garlic contains compounds that can stimulate nitric oxide production and promote cardiovascular health.
• Citrus fruits: Oranges, lemons, and other citrus fruits are rich in vitamin C, which can help support nitric oxide production.
• Pomegranate: Pomegranate juice and seeds contain antioxidants and nitrates that may support NO levels and cardiovascular health.
• Watermelon: Watermelon contains an amino acid called citrulline, which can be converted into arginine, a precursor to nitric oxide.
• Nitrates in Vegetables: Nitrates are compounds found in certain vegetables that can be converted into NO in the body. Examples of nitrate-rich vegetables include spinach, arugula, kale, beetroot, and lettuce.
• Beets and Beetroot Juice: Beets and beetroot juice are well-known for their high nitrate content, which can be converted into nitric oxide.
• Dark Chocolate: Dark chocolate contains flavonoids, which have been shown to support nitric oxide production and cardiovascular health.

Interaction with other drugs

NO can interact with various drugs due to its role as a signaling molecule in many physiological processes. Some interactions include:

• Blood pressure medications: NO donors or drugs that increase NO levels, such as nitroglycerin or other nitrate medications, can enhance the effects of blood pressure-lowering medications like antihypertensives. This interaction can lead to excessive hypotension (low blood pressure).
• Erectile dysfunction drugs: Drugs used to treat erectile dysfunction, such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra), work by enhancing the effects of NO in the penis, leading to vasodilation and improved blood flow. Combining these drugs with other NO donors or medications that increase NO levels can potentiate their effects and may cause a dangerous drop in blood pressure.
• Anticoagulants and antiplatelet drugs: NO inhibits platelet aggregation and can increase bleeding risk. Combining NO donors or medications that increase NO levels with anticoagulants (e.g., warfarin, heparin) or antiplatelet drugs (e.g., aspirin, clopidogrel) may further enhance the risk of bleeding.
• Drugs affecting nitric oxide synthesis: Medications that affect the synthesis of NO, such as inhibitors of NO synthase (NOS), may interact with drugs that rely on NO signaling for their effects. These interactions can affect cardiovascular function, neurotransmission, and immune response.
• Alpha-blockers: Alpha-blockers, used to treat conditions like benign prostatic hyperplasia (BPH) and hypertension, can interact with NO donors or drugs that increase NO levels, leading to additive effects on blood pressure lowering.
• Drugs affecting cytochrome P450 enzymes: Some drugs can affect the activity of cytochrome P450 enzymes, which are involved in the metabolism of NO donors and other drugs. Interactions with these drugs can alter the metabolism and effectiveness of medications that affect NO levels.

Side effects

While NO is essential for various physiological functions in the body, including vasodilation and neurotransmission, excessive intake or production of nitric oxide can lead to potential complications. Here are some of the possible complications associated with taking excessive amounts of nitric oxide:

• Hypotension: Excessive nitric oxide can cause a significant drop in blood pressure (hypotension). This can lead to symptoms such as dizziness, lightheadedness, fainting, and in severe cases, shock.
• Headaches: Increased levels of nitric oxide can cause headaches, which may range from mild to severe and can be debilitating for some individuals.
• Increased bleeding risk: NO can inhibit platelet aggregation and contribute to increased bleeding risk. Excessive nitric oxide production may lead to prolonged bleeding and difficulty in clot formation.
• Worsening of respiratory conditions: In individuals with certain respiratory conditions such as asthma, excessive nitric oxide production can exacerbate symptoms by causing airway dilation and inflammation.
• Nitric oxide toxicity: In rare cases, excessive exposure to NO gas, particularly in industrial or occupational settings, can lead to toxicity, causing respiratory distress, lung damage, and even death.
• Formation of reactive nitrogen species: Excessive nitric oxide can react with other molecules in the body to form reactive nitrogen species, such as peroxynitrite, which can contribute to oxidative stress, tissue damage, and inflammation.

Prof. Dr. Emin ÖZBEK

Urologist

Istanbul- TURKIYE