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Signal cascade of nitric oxide (NO synthase)

What Is NO Synthesis?

Since the 1990s, nitric oxide, the chemical formula NO, has been of great interest as a biological molecule. NO is involved in the function of all major organ systems. ( Hampl2008odn ) In the world of medicinal plants of the adapogen group, NO research has brought a major breakthrough: it has helped to explain some previously unexplained effects. For example, in ginseng, due to the influence of the NO path, it was possible to explain its effect on 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 the property of nitric oxide, NO but of irritant nitrogen dioxide, NO 2 , to which the NO oxidizes in the presence of oxygen.

Nitric oxide is a radical (it 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 the college reader from Linde Healthcare , who pointed out the inaccuracies in the previous version of my text about NO and recommended to me academic specialists 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 has helped me in particular a pleasantly short syllabus of prof. Hamlet, which is referred to herein as the Hampl2008 reference code.

The harmlessness of physiological NO concentrations in the 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 him.

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 with regard to NO concentration and is almost completely no longer at low concentrations of NO (which is interesting). At physiological concentrations (<10μM), there is almost no activity. I do not claim any depth of knowledge in this respect, but if I understand 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 quantitatively the most represented in hemoglobin. Hemoglobin is degraded 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 thus 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 heightened blood vessel size.

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. NOS3 NO synthase use abundantly, 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. NOS3 is the most applied in some 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 the 2 -NADPH oxidase produced by the 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 in activated white blood cells, ie in the inflammation.

Regulation of vessel blood flow using NO

Ventricular plaque 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 vessel wall. This signal comes to the smooth muscles of the vessel. For example, if the blood flow accelerates, the cells of the placenta release more nitric oxide, causing relaxation of the smooth muscles, increasing the blood flow of the vessel, and then (as dictated by the Bernouilli equation) re-calming the blood stream at increased flow. This simple feedback ensures that the 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, nitric oxide works similarly to 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 mainly works by increasing the expression and activity of NOS3, cGMP production and 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 hence 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 gloss and other adapogenes were found on this path. Plants such as the earth bite or the arrowhead , as well as the well-known sildenafil (Viagra), in turn, amplify the NO receptor region , and their effect is added to the effects of NO synthase. Ginseng is best explored from all adapogenic and its mechanisms of action on the NO signaling pathway are 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 the action of panaxosides on endothelial NO synthase eNOS, the NOS3 gene. By 2013, over 78 scientific publications were available on this topic. 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 investigations began by measuring the effect of ginseng tincture, with the aid of radionuclides ([ 14C ] -L-arginine -> [ 14C ] -L-citrulline), showing 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 various models, such as the rabbit top body in vitro, followed. In particular, it is mainly ginsenoside Rb1 ( Yu2007spn ) and ginsenoside Rg1 ( Lu2004gra ). An increase in NOS3 expression can be blocked by an androgenic antagonist by nilutamide at least in Rb1, indicating the effect on the nuclear androgen receptor ( Yu2007spn ). Another panaxoside-related 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. In 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 the communication tasks, hemoglobin is eliminated. NO is only poisoned at 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