Key enzyme in arachidonic acid metabolism. ★★★FITNESS LIVE★★★Sports nutrition

To eicosanoids (είκοσι, Greek.-twenty) include oxidized derivatives of eicosanoic acids: eicosotriene(S20:3), arachidonic(S20:4), Timnodonova(C20:5) fatty acids. Eicosanoid activity varies considerably on the number of double bonds in the molecule, which depends on the structure of the original fatty acid.

There are three main groups of eicosanoids: prostaglandins, leukotrienes, thromboxanes.

Prostaglandins (Pg) are synthesized in almost all cells, except erythrocytes and lymphocytes. There are types of prostaglandins A, B, C, D, E, F. The functions of prostaglandins are reduced to changes in the tone of smooth muscles of the bronchi, genitourinary and vascular systems, and gastrointestinal tract, while the direction of changes varies depending on the type of prostaglandins, cell type and conditions . They also affect body temperature.

Prostacyclins are a subtype of prostaglandins (Pg I), cause dilatation of small vessels, but also have a special function - they inhibit platelet aggregation. Their activity increases with an increase in the number of double bonds in the original fatty acids. They are synthesized in the endothelium of myocardial vessels, uterus, and gastric mucosa.

Thromboxanes (Tx) are formed in platelets, stimulate their aggregation and cause vasoconstriction. Their activity is decreasing with an increase in the number of double bonds in the original fatty acids.

The total effect in the body prostacyclins And thromboxanes on thrombus formation and blood pressure add up. With a lack of polyunsaturated fatty acids in food, there is a bias towards the predominant activity of thromboxanes, which leads to an increase in blood viscosity, the formation of blood clots and spasm of small vessels, and, in general, to impaired peripheral circulation. The entry of ω3-fatty acids into cells counteracts these pathological changes.

Leukotrienes (Lt) are synthesized in leukocytes, in the cells of the lungs, spleen, brain, and heart. There are 6 types of leukotrienes A, B, C, D, E, F. In leukocytes, they stimulate motility, chemotaxis and migration of cells to the site of inflammation; in general, they activate inflammatory reactions, preventing its chronicity. They also cause contraction of the bronchial muscles (in doses 100-1000 times less than histamine).

Eicosanoids cannot be deposited; they are destroyed within a few seconds, and therefore the cell must constantly synthesize them from incoming ω6- and ω3-series fatty acids.

The source of free eicosanoic acids are cell membrane phospholipids.

Influenced histamine, complex antigen-antibody, cytokines, kinins phospholipase A 2 or a combination of phospholipase C and DAG lipase are activated, which cleave the fatty acid from the C 2 position of membrane phospholipids.

Synthesis of eicosanoids using the example of arachidonic acid

Polyunsaturated fatty acid is metabolized mainly in two ways: cyclooxygenase And lipoxygenase, the activity of which is expressed to varying degrees in different cells. The cyclooxygenase pathway is responsible for the synthesis of prostaglandins and thromboxanes, the lipoxygenase pathway is responsible for the synthesis of leukotrienes.

Chemistry of reactions cyclooxygenase And lipoxygenase shown .

Drug regulation of synthesis

Adrenal cortex hormones glucocorticoids indirectly, through the synthesis of specific proteins, suppress the activity phospholipase A 2 and hence the formation of all types of eicosanoids. This is the basis for the widespread use of cortisol drugs (prednisolone, dexamethasone) for the treatment of inflammatory, autoimmune and allergic conditions.

Nonsteroidal anti-inflammatory drugs(aspirin, indomethacin, ibuprofen) inhibit cyclooxygenase and reduce the production of prostaglandins and thromboxanes. They have found application as an antipyretic and in cardiology.

Blocking cyclooxygenase in the kidneys, as a side effect of salicylates, it causes a decrease in the synthesis of prostaglandins in the renal vessels and a decrease in blood circulation in the kidneys.

Depending on the source fatty acid, all eicosanoids are divided into three groups:

First group – synthesized from eicosotrienoic acid (C20:3), which is formed from linolenic acid (C18:3). In accordance with the number of double bonds, prostaglandins and thromboxanes are assigned index 1, leukotrienes - index 3: for example, Pg E1, Pg I1, Tx A1, Lt A3.
Interestingly, PgE1 inhibits adenylate cyclase in adipose tissue and prevents lipolysis; it is also involved in the pathogenesis of bronchospasm.
Second the group is synthesized from arachidonic acid (C20:4). According to the same rule, it is assigned an index of 2 or 4, for example, Pg E2, Pg I2, Tx A2, Lt A4.
Third The eicosanoid group comes from thymnodonic acid (C20:5). Based on the number of double bonds, indices of 3 or 5 are assigned: for example, Pg E3, Pg I3, Tx A3, Lt A5.

The division of eicosanoids into groups has clinical significance. This is especially evident in the example prostacyclins And thromboxanes:

The resulting effect dietary intake or pharmacological use of more polyunsaturated fatty acids is the formation of thromboxanes and prostacyclins with b O a larger number of double bonds, which changes the rheological properties of blood and reduces its viscosity, reduces thrombus formation, dilates small vessels and improves blood supply to tissues, reduces high blood pressure. All these effects are valuable for circulatory disorders, atherosclerosis, and cardiac patients.

Arachidonic acid (AA) is an omega-6 fatty acid, being the essential fatty acid when considering the ratio of omega-3 to omega-6 fatty acids (relative to fish oil fatty acids). It is pro-inflammatory and immunosupportive.

Pharmacological group: omega-6 fatty acids
Pharmacological action: synthesis of prostaglandins; increasing blood flow to muscles, increasing local sensitivity to IGF-L and , supporting satellite cell activation, cell proliferation and differentiation and increasing overall levels of protein synthesis and promoting muscle growth.

general information

Arachidonic acid (5-cis,8-cis,11-cis,14-cis-eicosantetraenoic acid) is an omega-6 fatty acid that serves as a major building block for the synthesis of prostaglandins (for example, PGE2 and PGF2a). These prostaglandins are integral to protein metabolism and muscle building, and perform important functions such as increasing blood flow to muscles, increasing local sensitivity to IGF-L and , supporting satellite cell activation, cell proliferation and differentiation, and increasing overall levels of protein synthesis and maintenance. muscle growth. Arachidonic acid serves as the primary thermostat for prostaglandin turnover in skeletal muscle tissue and is also responsible for initiating many of the immediate biochemical changes that occur during resistance exercise that ultimately lead to muscle hypertrophy. Thus, arachidonic acid is a highly anabolic substance.
Among the wide variety of supplements for athletes and bodybuilders, arachidonic acid, along with protein, is an essential substance for muscle growth.

Not to be confused with: linoleic acid (parent omega-6 fatty acid).

It is worth noting:

It is possible that arachidonic acid may worsen joint inflammation and pain.

Represents:

Muscle-forming substance.

Not compatible with:

Fish oil supplements (interfering with the ratio of omega-3 to omega-6 in favor of omega-6).

Arachidonic acid: instructions for use

There is not enough information at this time to recommend any ideal dosage of arachidonic acid, but a dosage of about 2000 mg taken 45 minutes before exercise is commonly used occasionally. It is unclear if this dosage is optimal, or for how long it is active. It is also worth noting that for individuals with chronic inflammatory diseases, such as rheumatoid arthritis or inflammatory bowel disease, the ideal dosage of arachidonic acid may need to be adjusted downward. In conditions of inflammatory diseases, the use of arachidonic acid may be contraindicated.

Sources and structure

Sources

Arachidonic acid (AA) is the most biologically relevant omega-6 fatty acid, and in the lipid membrane of the cell is the fatty acid that competes with two fish oil fatty acids (EPA and DGU) in determining the ratio of omega-3 to omega-6 fatty acids . Current evidence suggests that consuming 50-250 mg of arachidonic acid per day with some other sources adds up to a total of 500 mg per day; arachidic acid intake is usually less than that of vegetarians. Food sources of arachidonic acid include:

Arachidonic acid is found in the visible fat of meat products at the same level as meat; Despite the above indicators, it is unknown what happens to arachidonic acid during the cooking process. Some studies note an increase in fatty acids per weight during cooking, while others do not note any significant differences (relative to other fatty acids). Arachidonic acid is found naturally in foods, mainly in animal products. If arachidonic acid is not available in the diet, linoleic acid (the parent omega-6 fatty acid found in animal products) can be used to produce arachidonic acid in the body. Body AA concentrations follow a nonlinear dose-response relationship with dietary intake of linoleic acid (the parent omega-6 fatty acid), where human diets consisting of less than 2% linoleic acid contribute to increases in plasma arachidonic acid levels when supplemented with linoleic acid. acids; with a share of 6% (classical Western diet), this was not detected. On the other hand, dietary intake of arachidonic acid increases plasma arachidonic acid in a dose-dependent manner. Linoleic acid (the parent omega-6 fatty acid) obtained from food may increase plasma levels of arachidonic acid, demonstrating how omega-6 fatty acids mediate their effects. Apparently, at this stage there is a so-called limit, and the use of arachidonic acid allows you to bypass it, increasing plasma concentrations of arachidonic acid in a dose-dependent manner. Reducing the proportion of arachidonic acid in the diet slightly (244% instead of 217%) increases the amount of EPA contained in the membranes of red blood cells (with fish oil consumption) without affecting DHA.

Biosynthesis

Arachidonic acid is the reason that linoleic acid (a dietary source of omega-6 fatty acids) has the status of an essential fatty acid, since the latter is required in the diet to be converted into the previously mentioned one. In addition, arachidonic acid can be produced as a catabolite of anandamide (one of the main endogenous cannabinoids acting on the cannabinoid system, also known as arachidonoylethanolamide) through the enzyme FAAH, and may also have some properties similar to anandamide, such as effects on TRPV4 receptors. The endocannabinoid 2-arachidonoylglycerol can also be hydrolyzed to arachidonic acid by monoacylglycerol lipase or similar esterases. Arachidonic acid is also produced in the body when cannabinoids are broken down.

Regulation

Older rats and humans have lower levels of arachidonic acid in the body and neurons (in plasma membranes), which is associated with lower activity of the biosynthetic enzymes that convert linoleic acid to arachidonic acid. Arachidonic acid appears to be reduced in older subjects compared to younger subjects due to lower conversion of dietary linoleic acid to arachidonic acid.

Eicosanoids

Biological activation of eicosanoids

Eicosainodes are fatty acid metabolites that are derived from either arachidonic acid or eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA, two fish oil fatty acids, belong to the omega-3 fatty acid class). DHA, EPA and AA are typically found in the middle of the spinal triglycerides (at the sn-2 binding position) and are thus present in free form in the membrane, while the phospholipase A2 enzyme is activated; when this enzyme is activated (seizures, ischemia, NMDA receptor stimulation, as well as various inflammatory cytokines such as IL-1beta, TNF-alpha, PMA and stress cells), and due to the non-discriminatory nature of the phospholipase A2 enzyme (releasing DHA/ EPA and AA with such efficiency), the number of eicosainoids produced depends on the ratio of omega-3 to omega-6 fatty acids in the cell membrane. Eicosanoids are action molecules derived from long chain fatty acids, and the eicosanoids from arachidonic acid are released from the same enzyme as fish oil fatty acids. This step determines which eicosanoids will be used in cellular action, being the mechanism underlying the importance of the dietary ratio of omega-3 to omega-6 fatty acids (since the eicosanoids released in the cell reflect the ratio in the membrane). Like fish oil fatty acids, arachidonic acid can follow one of three pathways for release from the membrane, namely:

COX-dependent pathway for producing PGH2 (the parent of prostaglandins, and all prostaglandins are derivatives of this pathway); prostaglandins are signaling molecules with a pentacyclic structure (pentagonal) in the fatty acid side chain;

LOX-dependent pathway, which produces lipoxins and leukotrienes;

The P450 pathway, which is a downstream subject of either the epoxygenase enzyme (to produce epoxyeicosatrienoic acids or EETs) or the hydroxylase enzyme (to produce hydroxyzaeicosatrienoic acids or HETEs).

Arachidonic acid can take one of three routes once it is released; The COX-dependent pathway (for prostaglandins), the LOX-dependent pathway (for lipoxins and leukotrienes), or one of the two P450 pathways to form EET or HETE. All of these classes of signaling molecules are known as omega-6 eicosanoids.

Prostaglandins

After being released from the cell membrane by phospholipase A2, arachidonic acid is converted to prostaglandin H2 (PGH2) by endoperoxide H synthases 1 and 2 (alternative names for the cyclooxygenase enzymes COX1 and COX2); This process involves the use of oxygen molecules to convert arachidonic acid into the unstable peroxide intermediate PGG2, which is then passively converted to PGH2; PGH2 serves as an intermediate parent for all AA-derived prostaglandins (a subset of eicosanoids). This first step in eicosanoid synthesis is one of the reasons for the anti-inflammatory and antiplatelet effects of COX inhibitors (eg, aspirin), which prevents AA eicosanoids from reducing PGH2 production. With respect to the enzymes that mediate this conversion, COX2 is an inducible form that can be activated in response to inflammatory stresses within 2-6 hours in a variety of cells, although it may be expressed under basal conditions in some cells (brain, testis, kidney cells , are known as dense spots), while COX1 is only generally expressed in all cells; this is due to variation in COX2, which is an inducible variant, and COX1 is a constitutive variant. Arachidonic acid (AA) is released from the cell membrane by phospholipase A2, then converted to PGH2 (prostaglindin) by one of two COX enzymes. Inhibition of this step inhibits the production of all AA-derived eicosanoids, and PGH2 is then synthesized to other eicosanoids. PGH2 can be converted to prostaglandin D2 by the enzyme prostaglandin D synthase (in the presence of sulhydryl compounds), and PDG2 is known to act through the DP2 receptor (originally studied on T cells and known as CRTh2, related to GRP44, binding to Gi proteins or G12). In this sense and due to signaling through its receptor, PGD2 is biologically active. PGD2 can be converted to PGF2alpha, which binds to its receptor (PGF2alpha receptor) in the same way as the DP2 receptor, although 3.5 times weaker than PGF2. The PGF2alpha isomer known as 9alpha, 11beta-PGF2 can also be derived from PGD2, being equivalent to the DP2 receptor. PGH2 can be converted to prostaglandin D2, which is one of several metabolic "branches" of prostaglandins. Once converted to PGD2, further metabolism of 9alpha, 11beta-PGF2 and PGF2alpha occurs, which can produce the effects of all three molecules. PGH2 (the parent prostaglandin) can thus be converted to prostaglandin E2 (PGE2) by the enzyme PGE synthase (of which the membrane binds mPGES-1 and mPGES-2 and cytosolic cPGES), with further metabolism of PGE2 leading to the formation of PGF2. Interestingly, selective inhibition of the inducible enzyme (mPGES-1) appears to attenuate PGE2 production without affecting the reduction in concentrations of other PGH2 prostaglandins, which in a non-discriminatory manner inhibits COX enzymes, which in turn inhibit all prostaglandins; inhibition of PGE2 production causes slight recompensation and an increase in PGI2 levels (due to COX2). PGE2 is generally implicated in the nature of pain as it is expressed through sensory neurons, inflammation, and potential loss of muscle mass. There are four receptors for prostaglandin E2, called EP1-4, each of which is a G protein receptor. EP1 is coupled to the Gq/11 protein, and its activation can increase phospholipase C activity (producing IP3 and diacylglycerol by activating protein kinase C). EP2 and EP4 receptors in combination with Gs protein can activate adenyl cyclase (creatine cAMP and protein kinase A activation). EP3 receptors appear to be slightly more complex (splicing time alpha, beta and gamma variants; EP3alpha, EP3beta and EP3gamma), all combined with Gi, which inhibits adenyl cyclase activity (and thus opposes EP2 and EP4) , with the exception of EP3gamma, which binds to the Gi and Gs proteins (inhibition and activation of adenyl cyclase). A group of enzymes known as PGE synthase, but specifically mPGES-1, converts the parent prostaglandin into PGE2, which plays a role in promoting inflammation and pain perception. PGE2 activates prostaglandin E receptors (EP1-4). PGH2 (parent prostaglandin) can be subject to the enzyme prostacyclin synthase and can be converted to a metabolite known as prostacyclin or PGI2, which is then converted to 6-keto-PGF1alpha (then converted to a urinary metabolite known as 2,3-dinor-6-keto Prostaglandin F1alpha). PGI2 is known to activate the prostanoid I (PI) receptor, which is expressed in the endothelium, kidney, platelets and brain. Prostacyclin production impairs the pro-platelet function of thromboxanes (see next section). PGH2 can be converted into PGI2, which is also called prostacyclin, and this prostaglandin then acts through the PI receptor. There is some association with the prostaglandin class, which is still based on the parent prostaglandin, with PGH2 acting as the subject of an enzyme known as thromboxane synthase, which is converted to thromboxane A2. Thromboxane A2 (TxA2) acts through T-prostanoid (TP) receptors, which are G protein-coupled receptors with two splice variants (TPalpha and TPbeta) coupled to Gq, G12/13. Thromboxane A2 is best known for its production in activated platelets during periods when platelets are stimulated and arachidonic acid is released, and its inhibition by COX inhibitors (namely aspirin) underlies the antiplatelet effects of COX inhibition. Thromboxane A2 is a metabolite of the parent prostaglandin (PGH2) that acts on T-prostanoid receptors, best known to form platelets, to enhance blood clotting (inhibition of thromboxane A2 underlies the antiplatelet benefits of aspirin).

Epoxy/Hydroxyeicosatrienoic acids

Epoxyeicosatrienoic acids (EET) are eicosanoid metabolites that are produced when arachidonic acid is a subject of the P450 pathway and then immediately subject to the epoxygenase enzyme; Hydroxyeicosatrienoic acids (HETE) are also metabolites of the P450 pathway, but are subject to the hydroxylase enzyme instead of the epoxygenase enzyme. HETE includes mainly 19-HETE and 20-HETE. EET includes 5,6-EET (which is converted to 5,6-DHET by the soluble enzyme epoxide hydroxylase), 8,9-EET (also converted, but to 8,9-DHET), 11,12-EET (to 11 ,12-DHET) and 14,15-EET (14,15-DHET). The P450 pathway mediates the synthesis of EET and HETE.

Leukotrienes

LOX pathway (to confirm, prostaglandins are due to the COX pathway, and EET and HETE are due to the P450 pathway) the main metabolites of eicosanoids are leukotrienes. Arachidonic acid is directly converted by LOX enzymes to a new metabolite, 5-hydroperoxyeicosatrienoic acid (5-HPETE), which is then converted to leukotriene A4. Leukotriene A4 can take one of two routes: either conversion to leukotriene B4 (LTB4) by the addition of a water group, or conversion to leukotriene C4 by glutanione S-transferase. If it is converted to a C4 metabolite, it can then convert to leukotriene D4 and then to leukotriene E4. Leukotrienes can form near nuclei. The LOX pathway typically mediates the synthesis of leukotrienes.

Pharmacology

Blood serum

Supplementation of 240–720 mg arachidonic acid in older adults for 4 weeks may increase plasma membrane arachidonic acid concentrations (within 2 weeks with no subsequent effect at 4 weeks), but there was no significant effect on urinary metabolites in serum PGE2 and lipoxin A4. . Arachidic acid intake does not necessarily increase plasma levels of eicosanoid metabolites, despite increasing arachidonic acid concentrations.

Neurology

Autism

Autism spectrum disorders are neurological conditions typically associated with impairments in social functioning and communication. Arachidonic acid, as well as DHA from fish oil and AA, have been studied to be critical for neuronal development in newborns; Disturbances in the metabolism of polyunsaturated fatty acids are known to be associated with autistic disorders (somewhat unreliable data). Supplementation of 240 mg AA and 240 mg DHA (along with 0.96 mg antioxidant astaxanthin) for 16 weeks in 13 patients with autism (half the dose for ages 6 to 10 years) showed no reduction in SRS rating scale scores. and ABC for autism, although there was some improvement on the Social Isolation (ABC) and Connection (SHD) subscales, the percentage of patients experiencing a 50% reduction in symptoms was not significantly different than placebo. There is very limited evidence to suggest that arachidonic acid with DHA fish oil reduces autism symptoms, although there is some effectiveness in improving social symptoms, so more research is needed.

Memory and learning

Activation of phospholipase A2 has been noted to promote axonal growth while simultaneously damaging neurons and elongating them. These effects of eicosanoids (derived from arachidonic acid and fish oil, predominantly DHA), and arachidonic acid in general, are noted to promote axonal growth through the 5-LOX pathway with maximum effectiveness at 100 µM, although at high concentrations (10 mm) this pathway is neurotoxic due to excess oxidation (prevented by vitamin E). Neurite outgrowth may be associated with an effect on calcium channels. In the body, arachidonic acid plays a role in promoting neural development and lengthening, although unnaturally high concentrations of arachidonic acid appear to be cytotoxic. As noted in rats, the activity of the enzymes that convert linoleic acid to arachidonic acid decreases with age; Dietary ingestion of arachidonic acid in aged rats promotes cognitive development, and this effect was replicated in relatively healthy aged men with 240 mg of AA (due to 600 mg of triglycerides) as assessed by P300 amplitude and latency. By reducing arachidonic acid production during aging, arachidonic acid supplementation may have a role in enhancing cognitive performance in older adults (it is not yet clear if the effect extends to younger subjects; this seems unlikely).

Nerves

Activation of phospholipase A2 has been reported to be involved in immune cell communication and neuronal demyelination, possibly a COX-dependent mechanism, such as celecoxib (a COX2 inhibitor); this helps improve neural healing parameters. This process involves eicosanoids of omega-3 and omega-6 origin.

Cardiovascular diseases

blood flow

Arachidonic acid (4.28% of rat diet) appears to reverse the aging-associated increase in vasoconstriction induced by phenylephrine in rats through endothelial-dependent mechanisms; there is a slight increase in the acetylcholine-induced vasorelaxant effect; no beneficial effect was observed in young rats. When testing older adults (65 years on average), consuming 240 mg of arachidonic acid with 240 mg of DHA (one of the fatty acids in fish oil) for three months led to an improvement in coronary blood flow during periods of hyperemia, but not at rest. Arachidonic acid supplementation in old age may have a cardioprotective effect by promoting blood flow, although evidence in humans is very sparse.

Skeletal muscle and performance

Mechanisms

Arachidonic acid is thought to be an important element in relation to skeletal muscle metabolism, as phospholipids in the sarcoplasmic membrane are thought to be reflected in the diet; exercise itself appears to promote changes in muscle phospholipid content (independent of muscle fiber composition, associated with a lower ratio of omega 6 to omega 3 fatty acids); eicosanoids from arachidonic acid interact with muscle protein synthesis through receptors. Arachidonic acid affects muscle protein synthesis through a COX-2 dependent pathway (suggesting the involvement of prostaglandins), which is associated with an increase in prostaglandin E2 (PGE2) and PGF(2alpha), although incubation with isolated PGE2 and PGF(2alpha) does not fully reproduce the hypertrophic effects arachidonic acid. PGE2 and PGF(2alpha) are also induced by exercise (particularly when stretching muscle cells in vitro), and this is also observed in serum and intramuscularly (fourfold - from 0.95+/-0.26 ng per ml to 3.97+/-0.75 ng per ml) in exercising subjects, in whom normalization occurs one hour after completion of exercise. The ability of the stretch reflex to increase concentrations of PGE2 and PGF(2alpha) may simply be due to stretch increasing COX-2 activity. It is worth noting that consuming 1500 mg of arachidonic acid (compared to a control diet containing 200 mg) for 49 days was found to increase PGE2 secretion from stimulated cells immune system (50-100%) in relatively healthy young people, but the relevance of this fact in relation to skeletal muscle is not known. This study also notes that without stimulation, there was no difference between groups. However, there was a trend towards increased serum PGE2 concentrations, at least in trained men, when consuming 1000 mg arachidonic acid for 50 days. Arachidonic acid, through eicosainodes known as PGF(2alpha) and PGE2, stimulates the synthesis of muscle proteins. They are produced from arachidonic acid, but do not usually form their corresponding muscle-binding eicosanoids unless the cells are stimulated by a stressor (such as the stretch reflex on a muscle cell), which then induces their production. The PGF(2alpha) receptor (FP receptor) appears to be activated by COX1 inhibitors (acetaminophen used in this study), enhancing the effects of PGF(2alpha) which appears to underlie the improvements in muscle protein synthesis observed in older people when using anti-inflammatory drugs. Arachidonic acid supplementation does not appear to affect the number of FP receptors in young adults; While exercise itself may increase EP3 receptors, but not COX1 inhibitors and arachidonic acid, it appears to continue to influence the processes. However, use of COX2 inhibitors (in young adults) has been shown to reverse exercise-induced increases in PGF(2alpha) (ibuprofen and acetaminophen) as well as PGE2, which are thought to occur due to the conversion of PGH2 to these metabolites, depending on from COX2 activity. By producing these eicosanoids, which are dependent on COX2 enzymes, inhibition of this enzyme is thought to reduce the anabolic effects of exercise when taken before exercise. Arachidonic acid (like EPA from fish oil) has been noted not to attenuate glucose uptake in isolated muscle cells, and 10 µM fatty acids may attenuate saturated fat-induced insulin resistance; this phenomenon is observed when using saturated fats with 18 carbon chains or more, which does not seem to apply to polyunsaturated fatty acids of equal chain length; This is associated with an increase in intracellular ceramides, which contributes to the impairment of the effects of Akt, reducing GLUT4-mediated glucose uptake from insulin. Arachidonic acid and omega-3 polyunsaturated acids are associated with improved insulin sensitivity in muscle cells, which may be secondary to a reduction in saturated fat levels in the lipid membrane, reducing intracellular ceramide concentrations. It is possible that this is not related to eicosainodes or the ratio of omega-3 to omega-6 fatty acids.

At physical activity vasoactive metabolites are known to be released, which cause relaxation of blood vessels, from which, along with some general vasodilatory agents (nitric oxide, adenosine, hydrogen ions), prostanoids are also released. Serum arachidonic acid levels are acutely suppressed by exercise (normalizing within minutes); There are increases in several arachidonic acid eicosanoids, including 11,12-DHET, 14,15-DHET, 8,9-DHET, and 14,15-EET, cycling at 80% of VO2 max in an acute manner; Higher urinary concentrations of 2,3-dinor-6-keto-prostaglandin F1alpha (indicative of higher concentrations of PGI2 and 6-keto-PGF1alpha) were observed after at least 4 weeks of training in previously untrained youth.

Interventions

In a sample of 31 trained men subject to a weightlifting program and a specialized diet (500 kcal excess at 2 g protein per kg body weight) supplemented with either 1 g arachidonic acid or placebo, after 50 days a small increase in peak power was found (by 7.1%) and average power (3.6%) during Wingate testing; there is no positive effect on muscle mass or weight lifting (bench press or leg press).

Bone metabolism and skeleton

Mechanisms

Prostaglandin F2 alpha (PGF2alpha) is capable of positive effects on bone growth due to its action as a mitogen on osteoclasts.

Inflammation and immunology

Arthritis

In patients with rheumatoid arthritis, reducing arachidonic acid from dietary sources (from 171 mg to 49 mg; the increase in eicosapentaenoic acid is minor) and linoleic acid (from 12.7 g to 7.9 g) can reduce pain symptoms associated with rheumatoid arthritis (by 15%), improving the effectiveness of fish oil consumption from 17% to 31-37%. Limiting dietary intake of arachidonic acid is thought to promote symptoms of rheumatoid arthritis by increasing the effectiveness of fish oil supplementation.

Interactions with hormones

Testosterone

Cortisol

In trained men, 1000 mg of arachidonic acid for 50 days did not result in significant changes in cortisol concentrations compared to placebo.

Interactions with the lungs

Asthma

Prostaglandin D2 (PGD2) is a potent substance on the bronchi, somewhat more powerful than the similar prostaglandin PGF2alpha (3.5 times) and much more powerful than histamine itself (10.2 times). Action through the DP-1 and DP-2 receptors is thought to mediate the pro-asthmatic effects of these prostaglandins, as these receptors, and their downregulation, are known to be associated with a reduction in airway inflammation. The eicosanoids arachidonic acid appear to be pro-asthmatic.

Interactions with aesthetic parameters

Hair

Prostaglandin D2 (from arachidonic acid) and the enzyme that makes it (prostaglandin D2 synthase) are 10.8 times higher in the scalp of men with androgenetic alopecia compared to areas of the scalp where there is hair; The substance appears to promote hair growth suppression by acting on the DP2 receptor (also known as GRP44 or CRTh2), with PGD2 receptor 1 not associated with hair growth suppression, and prostaglandin 15-ΔPGJ2 having suppressive effects. Excess enzyme is capable of mimicking androgenetic alopecia, suggesting the enzyme is a therapeutic target, and this enzyme is known to respond strongly to androgen exposure. Prostaglandin D2 and its metabolites (produced from prostaglandin H2 by the enzyme prostaglandin D2 synthase) are increased in areas of androgenetic alopecia compared to hairy areas; the enzyme itself increases the activity of androgens. Exposure through the DP2 receptor (named after prostaglandin D2) appears to inhibit hair growth. Exposure to prostaglandin F2alpha (PFG2alpha; binds to the PGF2alpha receptor at 50-100 nM) appears to mediate hair growth. There appears to be a greater presence of prostaglandin E2 (PGE2) in hairy areas of the scalp in balding men compared to balding areas (2.06-fold). An increase in PGE2 appears to be one of the possible mechanisms of minoxidil in promoting hair growth. Other prostaglandins are derived from arachidonic acid.

Safety and toxicology

Pregnancy

Arachidonic acid appears to increase in the mammary gland following oral intake (either from foods or supplements in a dose-dependent manner), although ingestion of DHA (from fish oil) alone may reduce arachidonic acid concentrations in the breast. breast milk. The increase was noted to be 14-23% after 2-12 weeks (consuming 220 mg arachidonic acid), while consuming 300 mg arachidonic acid for a week was found to be ineffective without significantly increasing concentrations. This apparent delay in effect is due to fatty acids obtained from the mother's so-called reserves rather than from her immediate diet. Concentrations of arachidonic acid in breast milk are correlated with diet, with some studies reporting low concentrations with reduced dietary intake of arachidonic acid overall; increased concentrations in breast milk are observed with increased intake of arachidonic acid. Arachidonic acid is known to accumulate in mothers' breast milk, and its concentrations in breast milk correlate with dietary intake.

R. Paul Robertson

Formation of eicosanoids. Prostaglandins, the first isolated metabolites of arachidonic acid, are so named because they were first identified in sperm. They were believed to be secreted by the prostate gland. As other active metabolites were identified, it became apparent that there were two main pathways for their conversion - cyclooxygenase and lipoxygenase. These synthesis routes are schematically presented in Fig. 68-1, and the structure of typical metabolites is in Fig. 68-2. All products of both cyclooxygenase and lipoxygenase origin are called eicosanoids. The products of the cyclooxygenase pathway - Prostaglandins and thromboxane - are prostanoids.

First stage synthesis in both metabolic pathways involves the cleavage of arachndonic acid from a phospholipid in the plasma membrane of cells. Free arachidonic acid can then be oxidized by the cyclooxygenase or lipoxygenase pathway. The first product of the cyclooxygenase pathway is the cyclic endoperoxide prostaglandin G 2 (PGG 2), which is converted to prostaglandin H 2 (PGN2). PGG 2 and PGN 2 serve as key intermediaries in the formation of physiologically active prostaglandins (PGD 2, PGE 2, PGF 2 and PGI 2) and thromboxane A2 (TCA2). The first product of the 5-lipoxygenase pathway is 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which plays the role of an intermediary in the formation of 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotrienes (LTA4, LTV 4, LTS 4, LTD 4 and LTE 4). Two fatty acids different from arachidonic acid, 3,11,14-eicosatrienoic acid (dihomo--linolenic acid) and 5,8,11,14,17-eicosapentaenoic acid, can be converted into metabolites. similar in structure to these eicosanoids. Prostanoid products of the first substrate are designated by index 1; the leukotriene products of this substrate are indexed 3. The prostanoid products of the second substrate are indexed 3, while the leukotriene products of this substrate are indexed 5.

Rice. 68-1. Diagram of arachidonic acid metabolism. Various medicines act on different enzymatic stages, inhibiting the reaction. The main metabolic pathways are cyclooxygenase and lipoxygenase. Phospholipase A 2 is inhibited by corticosteroids and mepacrine; cyclooxygenase - certain salicylates, indomethacin and ibuprofen; lipoxygenase - benoxaprofen and nordihydroguaiaretic acid (NDHA). Imidazole prevents the synthesis of TKA 2.

Arachidonic acid forms prostaglandins, designated by the index 2, and leukotrienes, designated by the index 4. The subscripts indicate the number of double bonds between carbon atoms in the side chains.

Virtually all cells possess the necessary substrates and enzymes for the formation of some metabolites of arachidonic acid, but differences in the enzyme composition of tissues cause differences in the products they form. Eicosanoids are synthesized as they are immediately needed and are not stored in significant quantities for subsequent release.

Cyclooxygenase products. Prostaglandins D 2, E 2, F 2 and I 2 are formed from the cyclic endoperoxides PGG 2 and PGH 2. Of these prostaglandins, PGE 2 and PGI 2 have the widest spectrum of physiological effects. PGE 2 has a noticeable effect within tissues and is synthesized by many of them. PGI 2 (also called prostacyclin) is the major product of arachidonic acid in endothelial and smooth muscle cells of the vascular wall and in some nonvascular tissues. PGI 2 serves as a vasodilator and inhibits platelet aggregation. It is believed that PGD 2 also plays a role in platelet aggregation and brain function, and PGD 2 in the function of the uterus and ovaries.

Rice. 68-2. Structure of typical biologically active eicosanoids.

Thromboxane synthetase catalyzes the incorporation of an oxygen atom into the endoperoxide ring of PGN 2 to form thromboxanes. TKA 2 is synthesized by platelets and enhances platelet aggregation.

Lipoxygenase products. Leukotrienes and GETE are the end products of the lipoxygenase pathway. Leukotrienes have histamine-like effects, including inducing vascular hyperpermeability and bronchospasm, and appear to influence leukocyte activity. LTC 4, LTD 4 and LTE 4 have been identified as slow reacting agents of anaphylaxis (MRV-A). (The pathophysiology of leukotrienes is discussed in detail in Chapter 202.)

The effect of drugs on the synthesis of eicosanoids. Many drugs block the synthesis of eicosanoids by inhibiting one or more enzymes in the pathways of their biosynthesis. Glucocorticoids and antimalarials, such as quinine, interfere with the cleavage of arachidonic acid from phospholipids (see Fig. 68-1). Cyclooxygenase is directly inhibited by non-steroidal anti-inflammatory drugs, including salicylates, indomethacin and ibuprofen. Benoxaprofen, another non-steroidal anti-inflammatory drug, inhibits the lipoxygenase-mediated conversion of arachidonic acid to GPETE. The antidepressant transamine inhibits the conversion of cyclic endoperoxides to PGI 2, and imidazole inhibits the synthesis of thromboxane. The fact that a drug inhibits the synthesis of a particular eicosanoid does not mean that the action of that drug directly leads to a deficiency of that product. Most of these drugs of this kind inhibit the early stages of the synthesis pathways and therefore block the formation of not one, but several products. In addition, some of these drugs have other effects. For example, indomethacin not only inhibits the formation of cyclic endoperoxides carried out by cyclooxygenase, but can also disrupt calcium transport across membranes, inhibit cyclic adenosine monophosphate (cyclic AMP)-dependent protein kinase and phosphodiesterase, and also inhibit one of the enzymes responsible for the breakdown of PGE 2 . There is no truly specific synthesis inhibitor and no specific receptor antagonist for individual arachidonic acid metabolites that could be used for therapeutic purposes. The lack of such drugs is an important barrier to establishing the role of these metabolites in physiological and pathophysiological processes.

Metabolism and quantitative analysis of eicosanoids. Arachidonic acid metabolites rapidly disseminate in vivo. Prostaglandins of the E and F series, although they are chemically stable substances, are almost completely broken down during passage through the liver or lungs. Thus, essentially the entire amount of unmetabolized PGE 2 determined in the urine is formed as a result of secretion from the kidneys and seminal vesicles, while the metabolites of PGE 2 contained in the urine characterize its synthesis (PGE3) throughout the body. Both PGI 2 and TKA 2 are chemically unstable and also undergo rapid dissimilation. Since the lifespan of PGE 2 , PGI 2 and TKA 2 in vivo is short, measurement of the amount of their inactive metabolites is usually used as an indicator of the rate of their formation. PGE 2 is converted to 15-keto-13,14-dihydro-PGE 2; PGI 2 - in 6-keto-PGF 1, and TKA 2 - in TKV 2. There are five methods for measuring the content of arachidonic acid metabolites in physiological fluids: quantitative determination of biological activity, radioimmunoassay, chromatographic method, determination of the number of receptors and mass spectrometry. When using any of these methods, certain precautions must be taken when handling body fluid samples because prostaglandin synthesis may be increased during collection of these samples. For example, if the blood has clotted or platelets have not been carefully separated from the plasma, the formation of large amounts of PGE 2 and TKA 2 during the test may lead to erroneous results. Adding a prostaglandin synthesis inhibitor to the blood collection tube will minimize this problem.

Physiology. Prostaglandins and leukotrienes have specific receptors on the plasma membranes of liver cells, corpus luteum, adrenal glands, lipocytes, thymocytes, uterus, pancreatic islets, platelets and erythrocytes. Most of these receptors have specificity for a certain type of eicosanoid. For example, the PGE receptor on the plasma membrane of liver cells binds high-affinity PGE 1 and PGE 2, but does not bind prostaglandins classes A, F and I. The post-receptor mechanisms by which the binding of prostaglandins alters cell function are not well understood. The normal physiological functioning of eicosanoids is not mediated through blood plasma. Instead, they act as local, intercellular and/or intracellular modulators of biochemical activity in the tissues in which they are produced (eg, paracrine function). Eicosanoids are autocoids, not hormones. Most of them have a very short lifespan in the circulating blood due to their chemical instability and/or rapid breakdown.

Lipolysis. PGE 2, synthesized by lipocytes, has specific receptors in lipocytes and is a strong endogenous inhibitor of lipolysis. Since stimulation of lipolysis by hormones requires the formation of cyclic AMP, the interaction between PGE and adenylate cyclase has been studied in some detail. PGE inhibits lipolysis by reducing the formation of cyclic AMP in response to the actions of adrenaline, adrenocorticotropic hormone (ACTH), glucagon and thyroid-stimulating hormone (TSH). Thus, PGE may act as an endogenous antilipolytic substance by preventing hormone stimulation of cyclic AMP formation.

Insulin and PGE may act independently of each other in their antilipolytic effects on lipocytes. For example, insulin, but not PGE, inhibits stimulation of lipolysis by exogenous cyclic AMP in isolated lipocytes, but both inhibit hormone-stimulated cyclic AMP formation. This suggests that the site of insulin action is distal to the site of adenylate cyclase stimulation. In some animals, PGE inhibits glucagon-induced lipolysis, while insulin has no effect on this process.

Balance of sodium and water. The renin-angiotensin-aldosterone system serves as the main regulator of sodium homeostasis, and control of water balance is carried out mainly by vasopressin. Arachidonic acid metabolites affect both of these systems. PGE 2 and PGI 2 stimulate the secretion of renin, and inhibitors of prostaglandin synthesis have the opposite effect. PGE 2 and PGI 2 reduce renal vascular resistance and increase renal blood flow; this leads to a redistribution of blood flow from the outer layer of the renal cortex to the juxtamedullary region of the kidneys. Inhibitors of prostaglandin synthesis, such as indomethacin and meclofenamate, on the contrary, reduce total renal blood flow and shunt the remaining part of it to the outer layer of the renal cortex, which can lead to acute renal vasospasm and acute renal failure, especially with a decrease in circulating blood volume and edematous conditions. PGEg is a natriuretic, while cyclooxygenase inhibitors cause sodium and water retention in the body.

Indomethacin also increases sensitivity to exogenous vasopressin, for example in dogs. Conversely, PGE 2 reduces vasopressein-stimulated water transport. Since this action of PGE 2 is disrupted by the administration of dibutyryl cyclic AMP, it is most likely that PGE 2 will interfere with the stimulation of adenylate cyclase by vasopressin.

Platelet aggregation. Platelets have the ability to synthesize PGE 2, PGD 2 and TKA 2. The physiological significance of PGE 2 and PGD 2 in platelet function has not been established; TKA 2 is a strong stimulator of platelet aggregation; in contrast, PGI 2, formed in the endothelial cells of the walls of blood vessels, on the contrary, plays the role of a strong antagonist of platelet aggregation. TKA 2 and PGI 2 can exert their multidirectional effects, respectively reducing and increasing the formation of cyclic AMP in platelets.

Inhibitors of the synthesis of endogenous prostaglandins counteract platelet aggregation. For example, a single dose of acetylsalicylic acid can suppress normal platelet aggregation for 48 hours or more, presumably by inhibiting cyclooxygenase-mediated TKA 2 synthesis. The duration of the phase of inhibition of cyclooxygenase by a single dose of this drug in platelets is longer than in other tissues, since the platelet, unlike nucleated cells capable of synthesizing new proteins, does not have the appropriate structures for the formation of a new enzyme. Consequently, the action of acetylsalicylic acid continues until newly formed platelets are released into the blood. On the other hand, endothelial cells quickly restore cyclooxygenase activity after cessation of treatment and, thus, PGI 2 production is restored. This is one of the reasons that the body of patients taking acetylsalicylic acid is not predisposed to excessive thrombus formation. In addition, the platelet is more sensitive to the drug than the endothelial cell.

Damage to the endothelium can lead to platelet aggregation along the blood vessel wall, causing a local decrease in PGI 2 synthesis and thereby opening the possibility of excessive platelet aggregation at the site of damage to the vascular wall.

Effect on blood vessels. The vasoactive properties of arachidonic acid metabolites are among the most remarkable effects of these substances. PGE 2 and PGI 2 are vasodilators, and PGF 2, TKA 2 and LTS 4, LTD 4, LTE 4 are vasoconstrictors in most areas of the vascular bed. These properties appear to be the result of their direct action on the smooth muscles of the vascular wall. If systemic blood pressure is maintained within physiological norms, the vasodilating effects of arachidonic acid metabolites lead to an increase in blood flow. However, if blood pressure decreases, blood flow will decrease, since in systemic hypotension, catecholamine-induced vasoconstriction will compensate for the vasodilatory effect of prostaglandins. Thus, when assessing the effect of arachidonic acid metabolites on blood flow in the vascular bed of a particular organ, it is necessary to exclude significant changes in systemic blood pressure.

Effect on the digestive tract. Prostaglandins of the E series also affect digestion. Injection of any of the prostaglandins PPg or PGEg into the gastric artery of dogs causes an increase in blood flow and inhibition of acid secretion, and when orally Some PGE analogues simultaneously inhibit acid secretion and have a direct protective effect on the mucous membrane of the digestive tract. In in vitro experiments, prostaglandins stimulate the smooth muscle of the digestive tract and thereby increase its motor activity, but it is not entirely clear whether these effects have physiological significance.

Neurotransmission. PGE inhibits the release of norepinephrine from sympathetic nerve endings. The effect of PGE on the secretion of this neurotransmitter appears to occur at the presynaptic level, i.e., in the area of ​​the nerve ending located proximal to the synaptic cleft; it can be reversible by increasing the calcium concentration in the perfusion medium. Therefore, PGEg is able to suppress the release of norepinephrine by blocking the entry of calcium into the cell. Inhibitors of PGEg synthesis increase the release of norepinephrine in response to stimulation of adrenergic nerves.

Catecholamines have the ability to release PGEg from various tissues, and this occurs probably through an adrenergic-mediated mechanism. For example, in innervated tissues such as the spleen, nerve stimulation or injection of norepinephrine causes the release of PGEg. This release is blocked after denervation or administration of α-adrenergic blocking agents. Thus, the activating nerve stimulus causes the release of norepinephrine, which in turn stimulates the synthesis and release of PGEg; then PGEg via feedback acts at the presynaptic level on the nerve ending, reducing the amount of norepinephrine released.

Endocrine function of the pancreas. PGEg has both stimulating and inhibitory effects on insulin secretion by pancreatic β cells in vitro. In vivo, PGE 2 suppresses the insulin response to intravenous glucose. This suppression appears to be specific to glucose because the insulin response to other secretagogues is not altered by PGE 2. The assumption that endogenous PGE 2 in vivo inhibits insulin secretion is supported by studies of prostaglandin synthesis inhibitors. Typically, such drugs increase insulin secretion and increase carbohydrate tolerance. An exception is indomethacin, which suppresses glucose-induced insulin secretion and can cause hyperglycemia. These conflicting results from indomethacin studies are likely due to an effect other than cyclooxygenase inhibition. The lipoxygenase pathway appears to play a role in enhancing insulin secretion by participating in the stimulus-secretion process. In this case, the likely active product of arachidonic acid could be 12-HPETE.

Luteolysis. Hysterectomy during the luteal phase of the ovarian cycle in sheep results in preservation of the corpus luteum. This suggests that the uterus normally produces a luteolytic substance. It can be assumed that this substance is PGE 2, since it can cause regression of the corpus luteum.

Pathophysiology of arachidonic acid metabolites. In most cases, the development of any disease is accompanied by excessive high level production of arachidonic acid metabolites, but some disorders may be associated with a decrease in their production. The latter can occur as a result of: lack of intake of arachidonic acid (an essential fatty acid in food); damage to the tissue necessary for the synthesis of prostaglandins, or due to treatment with drugs that inhibit enzymes in the synthesis chain.

Bone resorption: hypercalcemia due to malignant disease (see also Chapters 303 and 336). Hypercalcemia develops in various malignant diseases of the parathyroid glands. In some cases, the cause may be an excess of parathyroid hormone as a result of either its autonomous production by the tissue of the parathyroid glands, or ectopic formation by the tumor itself. However, most patients with hypercalcemia due to malignancy do not have elevated plasma levels of parathyroid hormone, so the etiology of this hypercalcemia is an area of ​​increased interest.

Prostaglandin E 2 is a powerful trigger for bone resorption and the release of calcium from them. In animals suffering from hypercalcemia, which have had tumors transplanted, there is an increased production of PGE 2. Treatment of these animals with inhibitors of PGE 2 synthesis leads to a decrease in the concentration of this prostaglandin and a simultaneous decrease in the level of hypercalcemia. Similarly, in some patients suffering from hypercalcemia and malignant tumors, a large number of PGE 2 metabolites are determined in the urine, while in patients with normal calcium concentrations in the blood and suffering from similar malignant tumors, such an increase in the level of PGE 2 metabolites in the urine is not observed. Medicines that inhibit prostaglandin synthesis. reduce the concentration of calcium in the blood in some patients suffering from hypercalcemia caused by a malignant disease. Thus, approximately 5-10% of patients with hypercalcemia and malignant tumors have increased levels of PGE production, and they may be treated with drugs that inhibit prostaglandin synthesis.

The source of the excess amount of PGE 2 in the blood of such patients has not been identified. One would expect compensation for this excess by increased levels of PGE breakdown in the liver and lungs. However, it is possible that the tumor releases such large amounts of PGE 2 into the circulating blood that its breakdown in the liver and lungs is insufficient to compensate for this load. In the presence of metastases in the lungs, the venous outflow from these tumors can flow into the systemic circulation, bypassing the lung tissue. Another possible mechanism is bone metastasis. Tumor cells in culture synthesize PGE, metastatic tumor cells in bone can also synthesize this prostaglandin, which will act locally to cause bone resorption. Hypercalcemia due to malignancy may occur in the absence of visible bone metastases, although it should be noted that current clinical imaging techniques for such metastases, such as radionuclide scanning, may not be sensitive enough to detect many small lesions.

Bone resorption: rheumatoid arthritis and dental cysts (see Chapter 263). Excessive production of PGE 2 has been found to cause juxtaarticular osteoporosis and bone erosions in some patients with rheumatoid arthritis. Synovial membranes affected by rheumatism synthesize PGE 2 in tissue culture, the culture medium of which is capable of causing bone resorption; the addition of indomethacin to the culture medium for such cells blocks this resorption ability. Since indomethacin does not prevent bone resorption caused by previously formed PGE 2 , it is assumed that PGE 2 produced in the synovial membranes is responsible for this resorption activity.

Cells from benign dental cysts also cause bone resorption and synthesize PGE 2 in tissue culture. Again, the resorption caused by the medium from these cultures can be reduced by adding indomethacin to it before incubation. A similar problem is the resorption of bone tissue of the dental alveoli in patients suffering from periodontal disease, a common inflammatory gum disease. The levels of PGE 2 in the gums during inflammation are higher than in healthy tissues. Thus, it is likely that bone resorption from dental alveoli may be due, at least in part, to local excess production of these metabolites.

Barter syndrome (see Chapter 228). Barter syndrome is characterized by elevated plasma levels of renin, aldosterone, and bradykinin; resistance to the pressor effect of angiotensin; hypokalemic alkalosis and depletion of potassium reserves in the kidneys in the presence of normal blood pressure. The basis for the postulated role of prostaglandins in this disease is that PGE 2 and PGI 2 stimulate the release of renin and the pressor response to administered angiotensin is blunted by the vasodilatory effects of these prostaglandins. Increased renin release leads to increased secretion of aldosterol, which in turn may increase urinary kallikrein activity.

In accordance with this, increased levels of PGE 2 and b-keto-PGF 1 are noted in the urine of patients suffering from Barter syndrome. In such patients, hyperplasia of the interstitial cells of the renal medulla (which synthesize PGE in culture) was also detected. The identification of these facts led to attempts to treat this disease with inhibitors of prostaglandin synthesis. Indomethacin (and other inhibitors) eliminates virtually all disorders, with the exception of hypokalemia. Thus, prostaglandin (probably PGE 2 and/or PGI 2) may mediate some of the manifestations of Barter's syndrome.

Diabetes mellitus (see Chapter 327). Intravenous administration of large amounts of glucose to healthy individuals causes a sharp (first phase) increase in insulin secretion into the blood plasma, followed by a slower and more prolonged response (second phase of insulin secretion). In patients suffering diabetes mellitus type II (non-insulin dependent, the development of which begins in adulthood), there is no first phase of insulin release in response to glucose administration and there is an inconsistent degree of decrease in insulin secretion in the second phase. The insulin response to other secretagogues such as arginine, isarin, glucagon and secretin is maintained. Thus, diabetic patients appear to have a specific defect that prevents the normal perception of glucose signals. Since PGE inhibits glucose-induced insulin secretion in healthy people, then patients with type II diabetes mellitus were prescribed inhibitors of endogenous prostaglandin synthesis in order to determine whether insulin secretion was restored. Both sodium salicylate and acetylsalicylic acid increase basal levels of insulin in the blood plasma and partially restore the first phase of the insulin response to glucose; Insulin secretion increases and in the second phase, glucose tolerance increases.

Patent ductus arteriosus (see Chapter 185). Experiments on animals have established that the ductus arteriosus in sheep is sensitive to the vasodilatory properties of PGE2, and PGE-like substances are present in the tissues of the duct wall. Thus, an increased concentration of endogenous PGE 2 can keep the ductus arteriosus open in the prenatal period. Because prostaglandin synthesis inhibitors cause constriction of the ductus arteriosus in fetal sheep, attempts have been made to administer indomethacin to premature infants with isolated patent ductus arteriosus. After several days of such treatment, the lumen of the duct was closed in most children, although some of them required a second course of treatment, and in a small number of children, surgical ligation of the ductus arteriosus remained necessary. It is most likely to obtain a favorable result from treatment with indomethacin in children whose period of intrauterine development does not exceed 35 weeks.

Patients with birth defects Certain types of hearts require a patent ductus arteriosus to survive. This is vital in cases where the ductus arteriosus is the main conduit through which unoxygenated blood from the aortic arch reaches the lungs, such as pulmonary atresia and right atrioventricular atresia. Because PGE relaxes the smooth muscle in the ductus arteriosus in lambs, clinical attempts have been made to administer intravenous PGE to maintain a patent ductus arteriosus in lambs as an alternative to immediate surgery. Such administration of PGE causes a short-term increase in blood flow to the lungs and an increase in arterial oxygen saturation until the necessary corrective heart surgery can be performed. The presence of a significant volume of right-to-left shunting for such heart defects makes it possible to avoid the breakdown of intravenously administered PGE 2 in the lungs before it enters the ductus arteriosus. In this case, the nature of the disease itself facilitates the delivery of the drug to the site of its action.

Peptic ulcer (see Chapter 235). Increased secretion of acid in the stomach in people suffering from peptic ulcers contributes to damage to the mucous membrane of the organ. There are various analogues of PGE 2, which inhibit the secretion of hydrochloric acid in the stomach and are also cytoprotective in nature. These substances are more effective than placebos in relieving pain and reducing stomach acid secretion in people with peptic ulcers. In addition, an increase in ulcer healing, assessed endoscopically, was reported in patients receiving PGE analogues compared with patients receiving placebo.

Dysmenorrhea (see Chapter 331). As a rule, dysmenorrhea is associated with increased uterine contractility. The fact that some analgesics used to treat this disease also inhibit prostaglandin synthesis suggests that arachidonic acid metabolites may play a role in the pathogenesis of dysmenorrhea. Prostaglandins of the E and F series are present in the endometrium of women. Intravenous administration of either of them causes uterine contractions, and the levels of PGF and PGE in menstrual blood are reduced after the administration of prostaglandin synthesis inhibitors. The results of controlled studies comparing the effectiveness of prostaglandin synthesis inhibitors and placebo in women suffering from dysmenorrhea show greater symptomatic improvement after drug therapy.

Asthma (see Chapter 202).

Inflammatory response and immune response (see Chapters 62 and 260). Medicines such as acetylsalicylic acid have antipyretic, anti-inflammatory and analgesic effects. There are several arguments in favor of a connection between inflammation and arachidonic acid metabolites: 1 - inflammatory stimuli, such as histamine and bradykinin, simultaneously with induced inflammation, also cause the release of endogenous prostaglandins; 2 - leukotrienes C 4 -D 4 -E 4 have a stronger bronchospastic effect than histamine; 3 - some metabolites of arachidonic acid cause vasodilation and hyperalgesia; 4 - in the foci of inflammation the presence of PGE 2 and LTV 4 is detected; polymorphonuclear cells release these substances during phagocytosis, and they in turn cause chemotaxis of leukocytes; 5 - some prostaglandins cause an increase in vascular permeability, which is a characteristic feature of the inflammatory response leading to local edema; 6 - PGE-induced vasodilation is not eliminated by atropine, anaprilin, methysergide or antihistamines, which are known antagonists of other possible mediators of the inflammatory response; thus, PGE may have a direct inflammatory effect, and some inflammatory mediators may function to influence PGE release; 7 - some metabolites of arachidonic acid can cause pain in experimental animals and hyperalgesia, or increased pain sensitivity in humans; 8-PGE can lead to the development of fever after its administration into the ventricles of the brain or into the hypothalamus of experimental animals; 9 - pyrogenic substances cause an increase in the concentration of prostaglandins in the cerebrospinal fluid, while inhibitors of prostaglandin synthesis reduce the intensity of fever and reduce the release of prostaglandins into the cerebrospinal fluid.

Arachidonic acid metabolites also play a role in the immune response. Small amounts of PGE 2 can inhibit lymphocyte stimulation in humans caused by mitogenic substances such as phytohemagglutinin, and the inflammatory response may be associated with local release of arachidonic acid metabolites; thus, these substances may act as negative modulators of lymphocyte function. The release of PGE by mitogen-stimulated lymphocytes may represent part of a feedback control mechanism by which lymphocyte activity is realized. The sensitivity of lymphocytes to the inhibitory effect of PGE 2 in humans increases with age, and indomethacin increases the sensitivity of lymphocytes to the action of mitogens to a greater extent in older people. A culture of lymphocytes taken from patients suffering from lymphogranulomatosis releases more PGE 2 after the addition of phytohemagglutinin, and the sensitivity of lymphocytes increases under the influence of indomethacin. If suppressor T-lymphocytes are removed from the corresponding cultures, the amount of synthesized PGE 2 decreases, and the sensitivity of lymphocytes taken from patients with lymphogranulomatosis and from healthy people becomes the same. Suppression of cellular immunity in patients suffering from lymphogranulomatosis may be the result of inhibition of lymphocyte function by prostaglandin E.

Which refers to saturated Omega-6 acids. Experts are still debating how essential this substance is. After all, it is produced by the human body, although not in large quantities.

Arachidonic acid: where is it found?

There are plenty of sources for this component. Arachidonic acid is found in many foods: most of this substance is found in fatty foods. You can get it from eggs, wild meat or poultry, pork and red meat. It is worth noting that the substance is a component of fat even in lean dishes.

It is very important to adjust your diet, since arachidonic acid is found in the fats of those foods that a person eats daily. Excess of such substances can adversely affect health.

Of course, arachidonic acid, biological role which has not yet been fully studied, is a polyunsaturated acid. However, this substance should not be considered unconditionally useful. After all, this is a component of fats, the use of which in large quantities harms the body.

Biological role

Most of the properties of arachidonic acid have been proven. However, some of them still remain a mystery. Since this substance is an essential fatty acid, scientists are conducting clinical studies that focus on the effectiveness and role of the component in certain branches of modern medicine.

One of the directions is the effect of arachidonic acid on the progression of Alzheimer's disease. Research is currently being conducted in the early stages of this disease. However, there is already preliminary data that indicates that drugs based on this substance can be prescribed to prevent, as well as to slow down the progression of the disease in patients with an accurate diagnosis.

Arachidonic acid takes part in the synthesis of prostaglandin, which supports the functioning of muscle tissue. Specifically, such substances ensure proper relaxation and contraction of fibers during exercise. This function is important for every person, but especially for bodybuilders and athletes.

In addition, prostaglandins regulate the lumen of the vascular bed, and also contribute to the creation of blood vessels, exercise control over blood pressure, model inflammation in muscle tissue. Some forms of this substance improve blood clotting, while others, on the contrary, prevent blood clots in places where it is undesirable.

It is worth noting that arachidonic acid, the formula of which is C 20 H 32 O 2, helps prevent excessive production of hydrochloric acid in the digestive tract. In addition, the substance stimulates the synthesis of protective mucus, which prevents the development of peptic ulcers, as well as other problems associated with the gastrointestinal tract.

Another advantage of arachidonic acid is the regeneration and growth of muscle fibers and skeletal muscles. It is worth noting that without this substance normal physical development any child.

The ability of a substance to cause inflammation

As already mentioned, arachidonic acid promotes inflammation in muscles and other tissues. Of course, this does not always harm the body. The exception in this case is the presence of an inflammatory disease. It is possible to reduce the severity of this process in tissues. It is enough to take regular aspirin. If you don’t have tablets at hand, you can include in your diet foods that have an anti-inflammatory effect.

Processes in muscle fibers, caused by arachidonic acid, should be adopted by weightlifters and bodybuilders. There is speculation that the inflammation caused by this substance makes training more effective. After all, muscle tissue receives an additional signal.

Where is acid used?

Due to its properties, arachidonic acid, the formula of which is indicated above, received wide application. This substance is used to treat many ailments, including Alzheimer's disease, peptic ulcer, deterioration of memory and blood clotting, arterial hypertension, decreased mental abilities, decreased labor, as well as muscle weakness. Arachidonic acid causes inflammation in muscle tissue.

Side effects

The use of arachidonic acid has a positive effect on the condition of the body. However, the substance, like many others, has side effects. With frequent and uncontrolled use of arachidonic acid preparations, insomnia, impaired cerebral circulation, fatigue, heart disease, peeling skin, and brittle hair are observed. In addition, the substance stimulates labor and helps increase cholesterol levels in the blood.

(English abbr. ARA) - polyunsaturated fatty acid omega-6 20:4 (ω-6), plays an important role in the human body. Arachidonic acid is an essential fatty acid, meaning the body can synthesize it autonomously. Arachidonic acid is subject to oxidation by atmospheric oxygen, and therefore requires special storage conditions.
In the body, arachidonic acid is part of phospholipids (especially phosphatidylethanolamine, phosphatidylcholine), they are the backbone of cell membranes. Maximum amounts are found in the brain and muscles. Arachidonic acid is involved in cell signaling as an inflammatory mediator.

Arachidonic acid in foods
Arachidonic acid is present in greatest quantities in the brain, as well as in liver, meat and milk fat.

Arachidonic acid in bodybuilding
Arachidonic acid is needed for the restoration and growth of skeletal muscles. More recently, Mike Roberts of Baylor University conducted a study and published an article in the International Society of Sports Nutrition entitled "Arachidonic Acid, The New Mass Builder explaining the role of this nutrient in muscle anabolism, and its potential for the enhancement of muscle size and strength."
Mike Roberts states that main reason muscle growth is a local inflammation of muscle tissue, which arises as a result of microtrauma acquired as a result of physical exercise. This theory is supported today by many scientists. Roberts presented in his study that arachidonic acid is stored in large quantities in muscle tissue and is a source for the synthesis of prostaglandins, which cause local inflammation. In addition, the prostaglandin isomer PGF2a has the ability to stimulate muscle growth. Arachidonic acid is a regulator of local muscle inflammation and may be a major factor in the regulation of muscle anabolic processes in response to strength training.

Arachidonic acid cycle:
1. As a result of physical exercise, phospholipase A2 (or cPLA2 - intramuscular enzyme) is activated.
2. cPLA2 provokes the release of arachidonic acid into the cytoplasm of the muscle cell
3. Another intracellular enzyme, cyclooxygenase, catalyzes arachidonic acid to create prostaglandins (PGE2, PGF2a), which leave the cell and initiate a number of physiological reactions (vasodilation, increased blood circulation, inflammation, etc.)
4. Prostaglandins (especially the PGF2a isomer) bind to prostaglandin receptors on skeletal muscle cells and initiate a cascade reaction that generates muscle growth.
Arachidonic acid and PGF2a enhance ribosome function in muscle cells by activating enzymes of the phosphoinositol 3-kinase complex. New proteins are synthesized in the ribosomes of cells, which are supplied to the construction of new muscle cells.

PGF2a has been found to have a similar effect to insulin-like growth factor (IGF-1), which has a pronounced anabolic effect.
Another significant confirmation that arachidonic acid is effective for muscle growth was the study of Dr. Dr. Todd Trappe from Ball State University. He found levels of protein synthesis in athletes who were receiving drugs that inhibit prostaglandin synthesis (NSAIDs). As a result, in the group that did not receive the drug, protein synthesis increased by 76%, while in the group that took NSAIDs, protein synthesis remained at the original level.

Reasonable effects of arachidonic acid:
Forced recovery
Increase in strength indicators
Increased stamina
Muscle growth

Recommendations for use
To increase strength and gain muscle mass, arachidonic acid should be taken at a dose of 500 mg-1000 mg per day. When purchasing sports nutrition, pay attention to the doses; quite often they are not sufficient to obtain the appropriate effect.

Side effects and harm
Arachidonic acid is a natural product and is included in common products. Studies have shown that arachidonic acid is not harmful to health and has a low number of side effects. Due to its pro-inflammatory effect, arachidonic acid can cause side effects such as increased muscle pain after training, joint pain, and headache, but this is very rare.

You can buy it in the online sports nutrition store Fitness Live