Nitric oxide (NO) is a gas that functions as a neurotransmitter in the central nervous system and as a signaling molecule in the immune system.

In humans, NO has been shown to play an important role in cardiovascular health. For example, research has demonstrated a strong positive correlation between the level of NO in the blood and the degree of pain relief during childbirth. Just like many other neurotransmitters, NO activates specific receptors on the surface of cells, causing these cells to change their function.

NO activates a receptor called the soluble guanylate cyclase (sGC) the primary receptor for nitric oxide in the blood vessels. The sGC enzyme is a cytosolic protein that is ubiquitous in animal tissues and can convert guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). One of the key enzymatic functions of sGC is to increase cyclic GMP levels in cells, which in turn activate protein kinase G (PKG). PKG activation promotes vasodilation, which allows more blood to flow to the heart and other organs. This, in turn, results in better organ function and a higher level of well-being.

Sources Of Nitric Oxide

There are three main sources of nitric oxide. The first is the amino acid L-arginine, which functions as a precursor to nitric oxide. The second source is the enzyme nitric oxide synthase (NOS). The third source is the degradation of tetrahydrobiopterin (BH4) to L-nitrogen monoxide (NO) and L-amino acid oxidase (AAO). BH4 is a cofactor that acts as a link between tetrahydrobiopterin (BH4) and the enzyme guanylate cyclase (EC 4.6.1.2), which ultimately results in the synthesis of cGMP.

The enzyme NOS converts L-arginine to nitric oxide and L-citrulline. There are three isoforms of NOS: inducible NOS (iNOS or NOS1), endothelial NOS (eNOS or NOS3), and neuronal NOS (nNOS or NOS2). Endothelial NOS and neuronal NOS are produced in the body; inducible NOS is not. The three isoforms of NOS are expressed in different tissues, with specific functions and requirements, which are summarized in Table 1.

NO Inhibitors And Agonists

To better understand the roles of NO, several classes of compounds have been developed that can bind to it or affect it in some way.

One of the challenges in studying NO is differentiating its diverse effects in different cells and tissues. To help with this complexity, researchers have developed a variety of compounds that can be used to specifically inhibit or activate NO function in cells and animals. Several important drugs that work by altering the function of NO are listed in Table 2.

For example, the non-steroidal anti-inflammatory drug (NSAID) indomethacin can inhibit the production of cyclic GMP, which in turn leads to vasodilation and increased blood flow. The antibiotic linezolid can also inhibit iNOS expression, thereby decreasing the production of NO. The anticonvulsant drug levetiracetam increases the amount of NO produced by endothelial cells.

The Effect Of Nitric Oxide In The Cardiovascular System

In the cardiovascular system, NO plays an important role in multiple processes. This includes vasodilation, inhibition of platelet aggregation, inhibition of smooth muscle cell proliferation, and modulation of gene expression. The precise mechanisms by which NO exerts its effects in the cardiovascular system are not completely understood, but researchers have proposed several possibilities.

Direct Effect On Blood Vessels

Many studies have shown that NO directly affects the function of blood vessels. For example, as mentioned earlier, blood vessels in the brain have high levels of nNOS, which contributes to the formation of nitric oxide in the vicinity of neurons. So, it is not surprising that NO has been shown to modulate the contractility of cerebral arteries and inhibit the proliferation of smooth muscle cells in the walls of blood vessels. Interestingly, the direct effect of NO on blood vessels may be more pronounced in smaller vessels than in larger ones.

Indirect Effect On The Nervous System

It is well established that NO is a neurotransmitter that acts on specific receptors to modify neuronal function.

Neurons are very sensitive to changes in their environment, and these changes can lead to alterations in neuronal function. For example, when exposed to harmful stimuli, many neurons undergo apoptosis (cell death). However, neurons that are exposed to beneficial compounds or grown in a lab setting (in the absence of harmful stimuli) can exhibit changes in their phenotype. These changes can lead to improved function or even full regeneration of damaged tissue. In short, the indirect effect of NO on the nervous system is mainly mediated by changes in gene expression, which lead to changes in protein synthesis and ultimately, cell function.

The Effect Of Nitric Oxide In The Immune System

The immune system is one of the major sources of NO, which is formed by immune cells called macrophages. Macrophages are involved in the host’s defense against bacteria, viruses, and other pathogens as well as play a role in tissue homeostasis by removing dead cells and cellular debris. This process of macrophage activation is heavily reliant on environmental cues – mainly changes in the concentration of O2 and glucose – as well as multiple internal and external factors such as hormones, growth factors, and cytokines.

Interestingly, macrophages can also release NO in an autocrine manner, which suggests that they may have an additional role in its regulation. In addition to its function in the defense system, NO is involved in macrophage-mediated inflammation and pathogen control. Macrophages can release nitric oxide synthase in response to various stimuli, including bacterial endotoxin, interferon-gamma, and lipopolysaccharide from gram-negative bacteria. Some of these stimuli are well known pyrogens (heat-inducing compounds).

The biological effects of NO end either in cell death or cell survival, suggesting that this gas may play a role in determining the outcome of an organism’s response to infection. In fact, the role of NO in bacterial infections has been the subject of intense study. Several lines of evidence indicate that in certain bacterial species, especially those that infect the lungs, the cardiovascular system, and the gastrointestinal tract, NO may promote cell survival and even growth. Some researchers have suggested that high levels of NO in these locations may act as a “double-edged sword” and cause either pathological changes or protective ones, depending on the context.

How Does Nitric Oxide Work?

Just like other molecules in living organisms, nitric oxide is involved in several important cellular functions. Researchers are just beginning to understand the role this gas plays in health and disease. What is known is that NO binds to specific receptors, which alter the behavior of the cell. In this way, nitric oxide can affect a cell’s function and its interaction with other cells, both within a single organ and between organs in the body. This section will discuss the known functions of nitric oxide and how these functions contribute to an organism’s health or onset of disease.

Cellular Function

One of the major functions of nitric oxide is to mediate communication between cells. Like other molecules, nitric oxide is relatively unstable and short-lived (although it does exist for longer in some environments). Therefore, it is not surprising that this gas functions as a messenger, helping cells to communicate with each other. This function of nitric oxide is essential for maintaining homeostasis in multicellular organisms. For example, when endothelial cells in the lining of blood vessels are stimulated by blood-borne factors such as growth factors or inflammatory cytokines, they will begin to synthesize and secrete NO. This in turn helps to promote angiogenesis (the formation of new blood vessels), an important process for tissue regeneration and wound healing.

Regulation Of Angiogenesis

The formation of new blood vessels is also called angiogenesis. This process is tightly regulated by a balance between pro-angiogenic factors and anti-angiogenic factors. Interestingly, nitric oxide is known to play an important role in angiogenesis. The majority of evidence suggests that high levels of nitric oxide promote angiogenesis, but there are studies that show the opposite. So, while it appears that this gas is either beneficial or detrimental to angiogenesis, depending on the concentrations and timing in relation to the process, the evidence points toward its important regulatory function.

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