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Signal cascade of nitric oxide (NO synthase)

What Is NO Synthesis?

Since the 1990s, nitric oxide, the chemical formula of NO, has been of great interest as a biological molecule. NO participates in the function of all major organ systems. ( Hampl2008odn ) In the world of medicinal plants of the adapogen group, NO research has brought a great breakthrough: it has helped explain some unexplained effects. For example, in ginseng, due to its influence on the NO path, it was able to explain its effect on increasing potency , against hypertension and other civilization diseases. The effect on the NO pathway was then investigated with other adaptogens (eg glossy gloss). Sildenafil (Viagra) and its clones, nitroglycerin and other medicines also act on the nitric oxide signal pathway. Newer inhalation therapy is also used.

Nitric oxide - an endogenous free radical

Nitric oxide can easily be produced in the laboratory by reacting nitric acid with copper sawdust . But do not let it down - the odor and the brown color of the gas released in this reaction is not a characteristic of nitric oxide, NO but of irritant nitrogen dioxide, NO 2 , to which NO oxidizes in the presence of oxygen.

Nitric oxide is a radical (has 11 electrons) and as such is unstable. Free radicals are commonly regarded as harmful to the body, and it is therefore important to be interested in the basic chemical reactions of NO, the degree of its toxicity and its ultimate fate in the tissues. At this point, I would like to thank Linde Healthcare's collegial reader, who pointed out the inaccuracies in my previous version of the NO text, and recommended to me academic experts who devote themselves to nitric oxide: prof. MUDr. Jana Hergeta, DrSc. ( pdf ), Head of the Institute of Physiology, 2nd Faculty of Medicine, Charles University, and his colleague, prof. RNDr. Václav Hampla, DrSc ( pdf ). To answer the questions about toxicity and catabolism NO, the pleasant syllabus prof. Hamlet, which is referred to herein as the Hampl2008 reference code.

The harmlessness of physiological NO concentrations in tissue is completely unpredictable for evolutionary reasons, but it still requires mechanical explanation. The harmlessness of nitric oxide results from two facts:

  • Oxidation of NO is a higher order reaction which is very slow at physiological concentrations.
  • After the end of his role, NO is detoxified by hemoglobin, which oxidizes it to nitrate. The nitric anion is no longer a radical and our body is relatively capable of counseling.

Left to yourself, NO in the presence of oxygen naturally oxidizes to NO 2 . In solution, this oxidation is up to 200 times faster and the oxidation product is nitrite. However, this oxidation reaction is strongly cooperative in terms of NO concentration, and at low NO concentrations almost completely ceases (which is interesting). At physiological concentrations (<10μM), there is almost no exercise. I do not claim any depth of knowledge in this respect, but if I understand it correctly, NO, though reactive, can not easily react with ordinary biomolecules because of the splinter of its odd electron, and rather, it chooses special places like the atoms of metals in the enzyme reaction centers . In practice, NO usually ends with oxidation on the iron atom in the heme, which is the most quantitatively represented in hemoglobin. Hemoglobin degrades to methemoglobin, but with hemoglobin reductase, it soon recovers. ( Hampl2008odn )

Effects of NO - binding to guanylate cyclase

Guanylate cyclase plays a role in the target tissue of the nitric oxide sensor. NO binds to its heme and thereby activates the production of cyclic guanine monophosphate, cGMP. CGMP then initiates a variety of processes in the cell. For example, in smooth vascular muscles, cGMP leads to relaxation and hence increase the luminosity of the vessel.

CGMP is degraded after a certain period of time with phosphodiesterase. Sildenafil (Viagra) works by inactivating phosphodiesterase, and the cGMP produced in the cell lags longer than usual, resulting in NO signal amplification.

Synthesis of NO: three types of NO synthase

As a result of hemoglobin oxidation, nitric oxide is rapidly disappearing from the body and must be produced in real time. Three different NO synthases are encoded by three different genes - NOS2 (also inducible, iNOS) used by the immune system , NOS1 (also nNOS) used by neurons and NOS3 used by other cells. NO synthase NOS3 frequently uses, for example, vascular plaque cells (endothelium, hence the alternative name eNOS for NOS3). NO synthase NOS3 also contains cells of the pulmonary cells, mucous membranes of the airways, kidneys and genital glands. It is NOS3 that is most effective in the treatment of certain adaptogens.

Special functions NO: Bacteria poison

Special uses for the NO radical have white blood cells: they use it to kill bacteria. At the site of inflammation of the NO in conjunction with the superoxide radical with 2 -NADPH oxidase, the peroxynitrite anion OONO- is produced extremely quickly, which burns everything that comes in hand. NO white blood cell synthesis is called inducible because it is not very well expressed in normal circumstances - its expression is only increased with activated white blood cells, ie, inflammation.

Regulation of vessel blood flow through NO

Vessel cells have the ability to sense the strength of the blood stream and the amount of oxygen in the blood. Using NOS3, these cells release NO by signaling their measurements into deeper layers of the vascular wall. This signal comes to smooth blood vessels. For example, if the blood flow accelerates, the cells of the excretion release more nitric oxide, causing relaxation of the smooth muscles, increasing the lumen of the blood vessel, and then (as dictated by Bernouilli's equation) to re-calm the blood stream at increased flow. This simple feedback ensures that muscles and other parts of the body subject to increased exertion receive the proper supply of blood and oxygen. Nitroglycerin acts as a remedy against high blood pressure precisely because it releases NO in our body slowly, which causes vascular relaxation. The disadvantage of nitroglycerin is that NO is released not only in the blood vessels but throughout the body, which may not be entirely desirable.

NO and erection

Another important role of NO is the control of feeder vessels of the topical tissue - erection . Here the nitric oxide works similarly to the blood flow feedback. The difference is that NOS3 is in the erection under direct control of the parasympathetic nerves. When released nitric oxide is cracked into the vessels of the body, it increases their translucency and causes an erection ( Toda2005nop ). Technically interesting mechanics of erection I leave.

Stimulants NO Signaling - Viagra and Ginseng

Erectile medications are generally said to interfere with the erection signaling cascade described above and enhance one or more of their regulatory steps. Sildenafil (Viagra) works at a single point by increasing the sensitivity of smooth muscle cells to nitric oxide and some other signals. Ginseng in the erection pathway works mainly by increasing the expression and activity of NOS3, causing and cGMP degradation affects to a lesser extent if at all. Ginseng also improves libido.

The effect of ginseng on the synthesis of NO

Nitric oxide (NO) has become famous as a short-to-mid-range intercellular signal transducer. Nitric oxide regulates blood transfusion and therefore blood pressure , bronchial tract, and thus asthma , is responsible for pyre erection, plays a role in the formation of memory traces in the brain, in the capacity of sperm, in immunity ... Ginseng effects on the NO pathway are explained Its cardiovascular effects , well-known potency and other effects. To a lesser extent, gliding and other adaptogens were found on this path. Plants such as the earth bayonet or the arrowhead , as well as the well-known sildenafil (Viagra), in turn, amplify the NO receptor section and their effect is added to the effects of NO synthase. Ginseng is best explored from all adapogenic and its mechanism of action on the NO signaling pathway is well known.

Panaxosides amplify the eNOS pathway in the endothelium and elsewhere

In practice, most men after several days of ginseng use will notice gradual improvement in erection, blood pressure stabilization, and long-term protective and healing effects on vascular endothelium. Vasorelaxation and healing effect is due to panaxosides on endothelial NO synthase eNOS, the NOS3 gene. More than 78 scientific publications were available on the subject in 2013. So even those of us who do not believe in tradition can make sure that there are no superstitions or hypotheses but textbook facts.

Historically, these studies began by measuring the effect of ginseng tincture, with the aid of radionuclides ([ 14C ] -L-arginine -> [ 14C ] -L-citrulline), showed a vascular production of NO ( Chen1996cpg ). It was then found that the relaxing effect on the blood vessels can be blocked by nitro-L-arginine NO synthase inhibitor. Studies on different models, such as the rabbit top body in vitro, followed. In particular, it is mainly ginsenoside Rb1 ( Yu2007spn ) and ginsenoside Rg1 ( Lu2004gra ). Increase in NOS3 expression can be blocked by an androgenic antagonist by nilutamide at least in Rb1, indicating an effect on the nuclear androgen receptor ( Yu2007spn ). Another panaxoside associated with NO synthase is ginsenoside Re , which activates human sperm eNOS and may have a positive effect on fertility ( Zhang2006gif , Zhang2007grp ). It is not entirely clear whether panaxosides act by allosteric activation of eNOS or by changing its gene expression. For ginsenoside Re, Furukawa2006grm confirmed the activation of eNOS without change of expression, while Xia2011grp in ginsenoside Rb1 detected the ability to increase eNOS gene expression.

Activation of NO synthesis does not involve inflammatory iNOS

Nitric oxide, although radical, does not harm the body in physiological concentrations. After completing communication tasks, hemoglobin is eliminated. NO is poison only in high concentrations - white blood cells in this way, after activation with superoxide O 2- use against microbes. This process takes place only at the site of inflammation - only there is O 2- ( Hampl2008odn ). The source of NO for combat purposes is not eNOS (genus NOS3), but iNOS (genus NOS2). Because iNOS is expressed only when inflammation is called inducible - hence i . INOS is a two-armed weapon - effective against microbes, but dangerous in sterile inflammation such as myocardial infarction and stroke . Even a common hangover can actually be considered a mild sterile inflammation of the brain due to activation of the microglia .

While eNOS increases panaxoside, iNOS suppresses its anti-inflammatory effects . This is not a paradox, just one example of the contradictory effects of content ingredients that are typical of natural adaptogens.

| 30.11.2008