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Signaling cascade of nitric oxide (NO synthase)

What is it NO synthase?

Since the 90s, nitric oxide, a chemical formula NO, enjoys great popularity as a biological molecule. NO participates in the functions of all major organ systems. ( Hampl2008odn ) In the world of medicinal plants adaptogens NO research has brought great coup: We managed to use it to explain some previously unexplained effects. For example, in ginseng due to runway NO able to explain its effect to increase potency, antihypertensive and against other lifestyle diseases. Effect on NO pathway was then studied in other adaptogens (e.g. at lingzhi mushroom). On the signaling pathway of nitric oxide also acts sildenafil (Viagra) and its clones, nitroglycerin and other drugs . More recently, it is also used in inhalation therapy NO .

Nitric oxide - an endogenous free radicals

Nitric oxide can be easily prepared in the laboratory by reacting nitric acid with copper filings . Do not be mistaken - odors and brown color gas which in this reaction is not releasing properties of nitric oxide, NO, but irritable nitrogen dioxide, NO 2, in which NO in the presence of oxygen oxidizes.

Nitric oxide is a radical (has 11 electrons) and as such is unstable. Free radicals are normally deemed harmful substances the body, and it is therefore appropriate to wonder about 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 readers of kolegiálnímu of Linde Healthcare, who pointed me to the inaccuracies in the previous version of my text on NO and advised me of the academic experts who are dedicated to nitric oxide: prof. MD. Jan Herget, MD. , Head of the Institute of Physiology 2nd Faculty of Medicine , and his colleague, prof. RNDr. Vaclav Hampl . To answer questions about the toxicity and NO catabolism helped me especially pleasant brief syllabus prof. Hampl, who reference the code of Hampl2008odn .

A harmless physiological concentrations of NO in the tissue is evolutionary reasons completely unsurprising, but still requires a mechanistic explanation. Innocuity nitric oxide stems from two facts:

  • NO oxidation reaction is of a higher order, which is under physiological concentration of very slow.
  • After completing their role is NO detoxified hemoglobin which it is oxidized to nitrate. Nitrate anion radical and is no longer our body with it relatively can handle.

Left to himself, NO in the presence of oxygen naturally oxidized to NO 2. In solution, the oxidation up to 200 times faster and autoxidation products nitrite. This oxidation reaction is but in terms of concentration of NO strongly cooperative and at low concentrations of NO almost completely ceases (which is of interest). At physiological concentrations (<10 mm packing) does not take place almost entirely. Not claim in this respect no depth of knowledge, but if I understand correctly, so NO, although reactive, not due to spin his odd electron just as easily react with common biomolecules and respond chooses rather special places, such as metal atoms in reaction centers of enzymes . In practice, most often ends oxidation of NO to iron atom in heme, which is quantitatively the most represented in hemoglobin. Hemoglobin is degraded while on methemoglobin, but with the help of hemoglobin reductase again soon recovers. ( Hampl2008odn )

Effects of NO - binding to guanylate cyclase

Guanylate cyclase in the target tissue takes the role of nitric oxide sensor. NO binds to the heme and thus activates the production of cyclic guaninmonofosfátu cGMP. cGMP in the cell then triggers a variety of processes. For example, in smooth muscle cells leads to cGMP in relaxation, thereby increasing the inner diameter of the vessel.

cGMP is degraded after a certain time Phosphodiesterase. Sildenafil (Viagra) acts by phosphodiesterase inactivates and cGMP produced in the cell then lingers longer than usual, leading ultimately to amplify the NO signal.

NO synthesis: three types of NO synthase

As a result of the oxidation of nitric oxide by hemoglobin from the body rapidly disappears and must be produced in real time. To do this, we used three different NO synthase, encoded by three different genes - NOS2 (also inducible, iNOS) is used by the immune system , NOS1 (also nNOS) used by neurons and other cells used NOS3. NO synthase NOS3 widely used as cells in the vascular lining (endothelium, hence the alternative name for eNOS NOS3). NO synthase NOS3 contain cells of the alveoli, respiratory mucosa, kidney and gonads. Now NOS3 in the action of some adaptogens applies most.

Special features NO: poison bacteria

Special use for radical NO are white blood cells: use it to kill bacteria. At the site of inflammation in conjunction with NO radical superoxide O 2 supplied by NADPH oxidase extremely quickly create peroxynitritový OONO- anion, which burns about anything that comes to hand. NO synthase white blood cells called inducible, because they normally is not expressed - its expression increases only in activated white blood cells, i.e. involved in inflammation.

Regulation of vascular lumen using NO

Vascular Endothelial cells have the ability to feel the force of the blood flow and the amount of oxygen in the blood. With the help NOS3 these cells release NO, which indicate their measurements into the deeper layers of the vessel wall. This signal gets to smooth muscles of blood vessels. If, for example, accelerate blood flow, endothelial cells release more nitric oxide, which causes relaxation of smooth muscles, increases the lumen of the blood vessel and subsequent (as dictated Bernouilliho equation) re calming blood flow for increased flow. This simple feedback ensures that the muscles and other parts of the body subject to increased strain get proper blood and oxygen supply. Nitroglycerin works as a remedy for high blood pressure, precisely because in our body slowly releases NO, which causes vascular relaxation. The disadvantage of nitroglycerin is that NO is released not only in the arteries but throughout the body, which may not be entirely desirable.

NO and erection

Another important role is NO control afferent vascular erectile tissue - erection . Here nitric oxide works similarly as in the feedback blood flow. The difference is that u is NOS3 erection under direct control of the parasympathetic nerves. When released nitric oxide in vascular připlaven topořivého body, increase their lumen thus causing an erection ( Toda2005nop ). Technically interesting aside from the mechanics of erection.

Stimulants NO signaling - Viagra and ginseng

About Medicines facilitating erection is generally possible to say that interfere with signaling cascade described above erection and enhance one or more of their regulatory levels. Sildenafil (Viagra) acts in a single point, by increasing the susceptibility of the target smooth muscle cells to nitric oxide and certain other signals. Ginseng in track erection works mainly by increasing the expression and activity NOS3 , the formation and breakdown of cGMP affect a lesser extent, if at all. In addition, ginseng also improves libido.

The effect of ginseng on the synthesis of NO

Nitric oxide (NO) is famous as a carrier of intercellular signals over short and medium distances. Nitric oxide regulates the lumen of blood vessels and thus blood pressure , the lumen of trachea and thus asthma , is responsible for the erection of penis, plays a role in the formation of memory traces in the brain, in sperm capacitation in immunity ... ginseng with effect on the NO explain its cardiovascular effects , well known potency and other effects. To a lesser extent effect on this track also found Reishi mushroom shiny and other adaptogens. Plants such as tribulus terrestris or epimedium swept , and a well-known sildenafil (Viagra) in turn reinforce the receiving part of the NO and their effect adds to the effects of NO synthase. Ginseng is all adaptogens best explored and its mechanisms of action on the signaling pathway of NO are well known.

Panaxosidy potentiate eNOS pathway in endothelial and elsewhere

In practice, most of the men after a few days of use ginseng sees gradual improvement in erectile function, stabilize blood pressure and even long-term protective and healing effect on the lining of blood vessels - the endothelium. Vasorelaxant and healing effect is due to the action of panaxosidů endothelial NO synthase eNOS gene NOS3. The 2013 was on the subject available to over 78 scientific publications . So even those of us who do not believe in the tradition, they can make sure that there is not a superstition or a hypothesis but a textbook facts.

Historically these surveys began measuring the effect of ginseng tincture, in which, with the help of radionuclides ([14 C] -L-arginine -> [14 C] -L-citrulline) showed a gain vascular NO production ( Chen1996cpg ). Thereafter, it was found that the relaxing effect on blood vessels can be blocked by the NO synthase inhibitor nitro L-arginine. Followed by studies in different models, for example, in the rabbit corpus cavernosum in vitro. Specifically, it is mainly ginsenoside Rb 1 ( Yu2007spn ) and ginsenoside Rg 1 ( Lu2004gra ). NOS3 increased expression can be in at least one Rb block androgen antagonist nilutamide, which indicates exposure to nuclear androgen receptor ( Yu2007spn ). Another Panaxosidy related NO synthase is ginsenoside Re , which activates eNOS human sperm and may have a positive effect on fertility ( Zhang2006gif , Zhang2007grp ). It is not entirely clear whether panaxosidy act allosteric activation of eNOS, or by altering its gene expression. For ginsenosides Re confirms Furukawa2006grm activation of eNOS expression unchanged, while Xia2011grp in ginsenosides Rb 1 found ability to increase gene expression of eNOS.

Activation of NO synthesis does not affect inflammatory iNOS

Nitric oxide, though radical body at physiological concentrations harm. After meeting the communication tasks can be disposed of hemoglobin. NO is a poison only at high concentrations - white blood cells in this way can, after activation of superoxide O 2 used against microbes. This process takes place only at the site of inflammation - there is only consisting of O 2- ( Hampl2008odn ). NO source for combat purposes is not eNOS (gen NOS3), but iNOS (NOS2 gene). As iNOS is expressed when inflammation is called inducible - hence. iNOS is a double-edged sword - effective against microbes, but dangerous in sterile inflammation, such as occur during heart attack and stroke . Even ordinary hangover can actually be considered a lightweight sterile inflammation of the brain due to the activation of microglia .

While the activity of eNOS panaxosidy increase, iNOS contrary, its anti-inflammatory effects suppress . This is not a paradox, only one example of conflicting effects of content components that are natural adaptogens typical.

| 30.11.2008