Physiological role of catecholamines. Effect on secretion

Some human hormones and connections endocrine system with the nervous system are presented in Fig. 13.2. Under direct control nervous system contains the adrenal medulla and hypothalamus; other endocrine glands are associated with the nervous system indirectly, through the hormones of the hypothalamus and pituitary gland. The cells of the hypothalamus synthesize special peptides - liberins (releasing hormones). In response to stimulation of certain brain centers, liberins are released from axons nerve cells hypothalamus, ending in the pituitary gland, and stimulate the synthesis and release of tropic hormones by pituitary cells. Along with liberins, the hypothalamus produces statins, which inhibit the synthesis and secretion of pituitary hormones.

central nervous system

Nervous relations

Nerve connections ___
	Hypothalamus		Antidiure-
			tic
			Oxytocyp		muscles of the uterus,
					mammary glands
			Melanocyte-
			stimulate-		Melanocytes
			stimulating hormone
			Prolactia		Mammary gland
Somatotropin
			Lutsinizi-		Folliculo-
	Corticotropin	Thyrotropin		stimulating
Brain		Thyroid			Testes
substance
	adrenal glands
adrenal glands
ADRENALIN	CORTISOL	THYROXINE ESTROGENS			ANDROGENS

Rice. 13.2. Connections between the endocrine and nervous systems. Solid arrows indicate the synthesis and secretion of the hormone, dotted arrows indicate the effect of the hormone on target organs

Classification of hormones by biological functions to a certain extent conditional, since many hormones are multifunctional. For example, adrenaline and norepinephrine regulate not only the metabolism of carbohydrates and fats, but also heart rate, smooth muscle contraction, blood pressure. In particular, for this reason, many hormones, especially paracrine ones, cannot be classified according to their biological functions.

Changes in hormone concentrations in the blood

The concentration of hormones in the blood is low, on the order of IO6-IO JJ mol/l. Half-life in the blood is measured in minutes, for some hormones - tens of minutes, less often - hours. An increase in the concentration of a hormone in the blood under the action of a corresponding stimulus depends on an increase in the rate of synthesis of the hormone or the rate of secretion of the hormone already present in the blood. endocrine cell hormone.

Steroid hormones are lipophilic substances that easily penetrate through cell membranes. Therefore, they do not accumulate in cells, and an increase in their concentration in the blood is determined by an increase in the rate of synthesis.

Peptide hormones are released into the blood with the participation of special secretion mechanisms. These hormones, after their synthesis, are included in secretory granules - membrane vesicles formed in the lamellar complex; the wasp hormone is released into the blood by fusion of granules with plasma membrane cells (exocytosis). Hormone synthesis occurs quickly (for example, a proinsulin molecule is synthesized in 1-2 minutes), while the formation and maturation of secretory granules require more time - 1-2 hours. The storage of the hormone in secretory granules ensures a rapid response of the body to the stimulus. : the stimulus accelerates the fusion of granules with the membrane and the release of stored hormone into the blood.

Synthesis of steroid hormones

The structure and synthesis of many hormones are described in previous sections. Steroid hormones are a group of compounds related in origin and structure: they are all formed from cholesterol. Intermediate products during synthesis steroid hormones Pregnenolone and progesterone serve (Fig. 13.3). They are formed in all organs that synthesize any steroid hormones. Further, the transformation paths diverge: in the adrenal cortex, cortisol (glucocorticosteroid) and aldosterone (mineralocorticosteroid) (C,-steroids) are formed, in the testes - male sex hormones (C19-steroids), in the ovaries, female sex hormones (C18-steroids) . Most of the arrows in the diagram hide not one, but two to four reactions. In addition, alternative pathways for the synthesis of some hormones are possible. In general, the pathways for the synthesis of steroid hormones form a rather complex network of reactions. Many intermediates of these pathways also have some hormonal activity. However, the main steroid hormones are cortisol (regulation of carbohydrate and amino acid metabolism), aldosterone (regulation water-salt metabolism), testosterone, estradiol and progesterone (regulation of reproductive functions).

As a result of inactivation and catabolism of steroid hormones, a significant amount of steroids containing a keto group at position 17 (17-ketosteroids) is formed. These substances are excreted through the kidneys. Daily excretion of 17-ketosteroids in adult woman is 5-15 mg, in men - 10-25 mg. The determination of 17-ketosteroids in urine is used for diagnosis: their excretion increases in diseases accompanied by overproduction of steroid hormones, and decreases in underproduction.

Progesterone (C21) Aldosterone (C21)

Rice. 13.3. Pathways for the synthesis of steroid hormones:

1,2 - in the adrenal cortex, testes and ovaries; 3, 4 - in the adrenal cortex; 5 - in the testes and ovaries; 6 - in the ovaries

Paracrine hormones

Cytokines

Cytokines are signaling molecules with paracrine and autocrine actions; they practically never exist in the blood in physiologically active concentrations (with the exception of interleukin-1). Dozens of different cytokines are known. These include interleukins (lymphokines and monokines), interferons, peptide growth factors, and colony-stimulating factors. Cytokines are glycoproteins containing 100-200 amino acid residues. Most cytokines are produced and act in many types of cells and respond to various stimuli, including mechanical damage, viral infection, metabolic disorders etc. The exception is interleukins (IL-1a and IL-1R) - their synthesis is regulated by specific signals and in a small number of cell types.

Cytokines act on cells through specific membrane receptors and protein kinase cascades, as a result, transcription factors are activated - enhancers or silencers, proteins that are transported into the cell nucleus, find a specific DNA sequence in the promoter of the gene that is the target of this cytokine, and activate or suppress gene transcription .

Cytokines are involved in the regulation of proliferation, differentiation, chemotaxis, secretion, apoptosis, inflammatory reaction. Transforming growth factor (TGF-β) stimulates the synthesis and secretion of extracellular matrix components, cell growth and proliferation, and the synthesis of other cytokines.

Cytokines have overlapping, but still different biological activities. Cells different types, or varying degrees differentiation, or being in different functional state may respond differently to the same cytokine.

Eicosanoids

Arachidonic acid, or eicosatetraenoic acid, 20:4 (5, 8, 11, 14), gives rise to a large group of paracrine hormones - eicosanoids. Arachidonic acid, which comes from food or is formed from linoleic acid, is included in the composition of membrane phospholipids and can be released from them as a result of the action of phospholipase A. Next, eicosanoids are formed in the cytosol (Fig. 13.4). There are three groups of eicosanoids: prostaglandins (PG), thromboxanes (TX), leukotrienes (LT). Eicosanoids are formed in very small quantities and, as a rule, have a short time life - measured in minutes or even seconds.

Leukotrienes

Rice. 13.4. Synthesis and structure of some eicosanoids:

1 - phospholipase A2; 2 - cyclooxygenase

in different tissues and different situations different eicosanoids are formed. The functions of eicosanoids are diverse. They cause smooth muscle contraction and constriction blood vessels(PGF2Ct, synthesized in almost all organs) or, conversely, relaxation of smooth muscles and vasodilation (PGE2, also synthesized in most organs). PGI2 is synthesized mainly in the vascular endothelium, inhibits platelet aggregation, and dilates blood vessels. Thromboxane TXA2 is synthesized mainly in platelets and also acts on platelets - it stimulates their aggregation (autocrine mechanism) in the area of ​​vascular damage (see Chapter 21). Thromboxane TXA2 also constricts blood vessels and bronchi, acting on smooth muscle cells (paracrine mechanism).

Eicosanoids act on target cells through specific membrane receptors. The connection of the eicosanoid with the receptor turns on the mechanism of formation of the second (intracellular) signal messenger; they can be cAMP, cGMP, inositol trisphosphate, Ca2+ ions. Eicosanoids, along with other factors (histamine, interleukin-1, thrombin, etc.), are involved in the development of the inflammatory response.

Inflammation is a natural response to tissue damage, initial link healing. However, sometimes the inflammation is excessive or too prolonged, and then it itself becomes pathological process, illness, and requires treatment. To treat such conditions, eicosanoid synthesis inhibitors are used. Cortisol and its synthetic analogs (dexamethasone, etc.) induce the synthesis of lipocortin proteins, which inhibit phospholipase A2 (see Fig. 13.4). Aspirin (a non-steroidal anti-inflammatory drug) acetylates and inactivates cyclooxygenase (Fig. 13.6).

Rice. 13.6. Inactivation of cyclooxygenase by aspirin

Catecholamine hormones - dopamine, norepinephrine and adrenaline - are 3,4-dihydroxy derivatives of phenylethylamine. They are synthesized in chromaffin cells of the adrenal medulla. These cells got their name because they contain granules that turn red-brown when exposed to potassium bichromate. Clusters of such cells were also found in the heart, liver, kidneys, gonads, adrenergic neurons of the postganglionic sympathetic system and in the central nervous system.

The main product of the adrenal medulla is adrenaline. This compound accounts for approximately 80% of all medulla catecholamines. Outside medulla adrenaline is not produced. In contrast, norepinephrine, found in organs innervated by sympathetic nerves, is formed predominantly in situ (~80% of the total); the rest of norepinephrine is also formed mainly in nerve endings and reaches its targets in the blood.

The conversion of tyrosine to epinephrine involves four sequential steps: 1) ring hydroxylation, 2) decarboxylation, 3) side chain hydroxylation, and 4) N-methylation. The catecholamine biosynthesis pathway and the enzymes involved in it are presented in Fig. 49.1 and 49.2.

Tyrosine - hydroxylase hydroxylase

Tyrosine is the direct precursor of catecholamines, and tyrosine hydroxylase limits the rate of the entire process of catecholamine biosynthesis. This enzyme is found both in free form and in a form bound to subcellular particles. With tetrahydropteridine as a cofactor, it performs an oxidoreductase function, converting L-tyrosine to L-dihydroxyphenylalanine (-DOPA). Exist different ways regulation of tyrosine hydroxylase as a rate-limiting enzyme. The most important of these is inhibition by catecholamines according to the principle feedback: catecholamines compete with the enzyme for the pteridine cofactor, forming a Schiff base with the latter. Tyrosine hydroxylase, in addition, is competitively inhibited by a number of tyrosine derivatives, including α-methyltyrosine. In some cases, this compound is used to block excess production of catecholamines in pheochromocytoma, however, there are more effective agents that also have less pronounced side effect. Compounds of another group suppress the activity of tyrosine hydroxylase by forming complexes with iron and thus removing the existing cofactor. An example of such a compound is a,-dipyridyl.

Catecholamines do not cross the blood-brain barrier and, therefore, their presence in the brain must be explained by local synthesis. In some diseases of the central nervous system, such as Parkinson's disease, there are disturbances in the synthesis of dopamine in the brain. Precursor to dopamine

Rice. 49.1. Biosynthesis of catecholamines. ONMT-phenylethanolamine-N-methyltransferase. (Modified and reproduced, with permission, from Goldfien A. The adrenal medulla. In: Basic and Clinical Endocrinology, 2nd ed. Greenspan FS, Forsham PH. Appleton and Lange, 1986.)

FA - easily crosses the blood-brain barrier and therefore serves effective means treatment of Parkinson's disease.

DOPA decarboxylase

Unlike tyrosine hydroxylase. Found only in tissues capable of synthesizing catecholamines, DOPA decarboxylase is present in all tissues. This soluble enzyme requires pyridoxal phosphate to convert -DOPa to -dihydroxyphenylethylamine (dopamine). The reaction is competitively inhibited by compounds that resemble α-DOPA, such as α-methyl-DOPA. Halogenated compounds form a Schiff base with -DOPA and also inhibit the decarboxylation reaction.

α-Methyl-DOPA and other related compounds, such as α-hydroxytyramine (derived from tyramine), α-methylyrosine, and metaraminol, have been used successfully to treat some forms of hypertension. The antihypertensive effect of these metabolites is apparently due to their ability to stimulate α-adrenergic receptors (see below) of the corticobulbar system in the central nervous system, which leads to a decrease in the activity of peripheral sympathetic nerves and lowering blood pressure.

Dopamine b-hydroxylase

Dopamine b-hydroxylase (DBH) is a co-oxidase mixed function, catalyzing the conversion of dopamine to norepinephrine. DBG uses ascorbate as an electron donor and fumarate as a modulator; The active site of the enzyme contains copper. DBG of adrenal medulla cells is probably localized in secretory granules. Thus, the conversion of dopamine to norepinephrine occurs in these organelles. DBG is released from adrenal medulla cells and nerve endings together with norepinephrine, but (unlike the latter) is not reuptaken by nerve endings.

Phenylethanolamine-N-methyltransferase

The soluble enzyme phenylethanolamine - -methyltransferase (PCMT) catalyzes the -methylation of norepinephrine to produce adrenaline in adrenaline-producing cells of the adrenal medulla. Since this enzyme is soluble, it can be assumed that the conversion of norepinephrine to adrenaline occurs in the cytoplasm. The synthesis of TYMT is stimulated by glucocorticoid hormones that penetrate into the medulla through the intraadrenal portal system. This system provides 100 times greater concentration of steroids in the medulla than in the systemic arterial blood. Such a high concentration in the adrenal glands is apparently necessary for the induction

The adrenal medulla produces a compound that is far from steroids. They contain a 3,4-dioxyphenyl (catechol) nucleus and are called catecholamines. These include adrenaline, norepinephrine and dopamine (3-hydroxytyramine).

The sequence of catecholamine synthesis is quite simple: tyrosine -> dioxyphenylalanine (DOPA) -> dopamine -> norepinephrine -> adrenaline. Tyrosine enters the body with food, but can also be formed from phenylalanine in the liver under the action of phenylalanine hydroxylase. The end products of tyrosine conversion in tissues are different. In the adrenal medulla, the process proceeds to the stage of adrenaline formation, in the endings of the sympathetic nerves - norepinephrine, in some neurons of the central nervous system, the synthesis of catecholamines ends with the formation of dopamine.

The conversion of tyrosine to DOPA is catalyzed by tyrosine hydroxylase, the cofactors of which are tetrahydrobiopterin and oxygen. It is believed that it is this enzyme that limits the rate of the entire process of catecholamine biosynthesis and is inhibited by the end products of the process. Tyrosine hydroxylase is the main object of regulatory influences on the biosynthesis of catecholamines. The conversion of DOPA to dopamine is catalyzed by the enzyme DOPA decarboxylase (cofactor pyridoxal phosphate), which is relatively nonspecific and decarboxylates other aromatic L-amino acids.

However, there are indications of the possibility of modifying the synthesis of catecholamines by changing the activity of this enzyme. Some neurons lack enzymes for further conversion of dopamine, and it is this that is the final product. Other tissues contain dopamine β-hydroxylase (cofactors - copper, ascorbic acid and oxygen), which converts dopamine into norepinephrine. In the adrenal medulla (but not in the endings of the sympathetic nerves) there is phenylethanolamine, a methyltransferase that forms adrenaline from norepinephrine.

The donor of methyl groups in this case is S-adenosylmethionine. It is important to remember that the synthesis of phenylethanolamine-N-methyltransferase is induced by glucocorticoids entering the medulla from the cortex through the portal venous system. This may be the explanation for the unification of the two various glands internal secretion in one organ. The importance of glucocorticoids for the synthesis of adrenaline is emphasized by the fact that the cells of the adrenal medulla that produce norepinephrine are located around arterial vessels, while adrenaline-producing cells receive blood mainly from venous sinuses, localized in the adrenal cortex.

The breakdown of catecholamines occurs mainly under the influence of two enzyme systems: catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The main pathways for the breakdown of adrenaline and norepinephrine are schematically presented in Fig. 54. Under the influence of COMT in the presence of the methyl group donor S-adrenosylmethionine, catecholamines are converted into normetanephrine and metanephrine (3-O-methyl derivatives of norepinephrine and adrenaline), which, under the influence of MAO, transform into aldehydes and then (in the presence of aldehyde oxidase) into vanillylmandelic acid ( VMC) is the main breakdown product of norepinephrine and adrenaline. In the same case, when catecholamines are first exposed to the action of MAO, and not COMT, they are converted into 3,4-dihydroxymandealdehyde, and then, under the influence of aldehyde oxidase and COMT, into 3,4-dihydroxymandelic acid and VMC. In the presence of alcohol dehydrogenase, 3-methoxy-4-hydroxyphenylglycol can be formed from catecholamines, which is the main end product of the degradation of adrenaline and norepinephrine in the central nervous system.

Rice. 54. Metabolism of catecholamines.
COMT—catechol-O-methyltransferase; MAO—monoamine oxidase; AO - aldehyde oxidase; AD—alcohol dehydrogenase.

The breakdown of dopamine proceeds similarly, with the exception that its metabolites lack a hydroxyl group at the β-carbon atom, and therefore homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylacetic acid is formed instead of HVA.

The existence of a quinoid pathway for the oxidation of catecholamine molecules is also postulated, in which intermediate products with pronounced biological activity can arise.

Norepinephrine and adrenaline formed under the action of cytosolic enzymes in the endings of the sympathetic nerves and the adrenal medulla enter the secretory granules, which protects them from the action of degradation enzymes.

The uptake of catecholamines by granules requires energy expenditure. In the chromaffin granules of the adrenal medulla, catecholamines are tightly bound to ATP (4:1 ratio) and specific proteins - chromogranins, which prevents the diffusion of hormones from the granules into the cytoplasm. The direct stimulus for the secretion of catecholamines is, apparently, the penetration of calcium into the cell, stimulating exocytosis (fusion of the granule membrane with cell surface and their rupture with the complete release of soluble contents - catecholamines, dopamine β-hydroxylase, ATP and chromogranins - into the extracellular fluid).

The synthesis of catecholamines occurs in the cytoplasm and granules of cells of the adrenal medulla (Fig. 11-22). Catecholamines are also stored in the granules.

Catecholamines enter granules by ATP-dependent transport and are stored in them in complex with ATP in a 4:1 ratio (hormone-ATP). Different granules contain different catecholamines: some contain only epinephrine, others contain norepinephrine, and others contain both hormones.

Hormone secretion from granules occurs by exocytosis. Catecholamines and ATP are released from the granules in the same ratio in which they are stored in the granules. Unlike sympathetic nerves, cells of the adrenal medulla lack a mechanism for reuptake of released catecholamines.

In blood plasma, catecholamines form a fragile complex with albumin. Adrenaline is transported mainly to the liver and skeletal muscles. Norepinephrine is formed mainly in organs innervated by sympathetic nerves (80% of the total). Norepinephrine reaches peripheral tissues only in small quantities. T 1/2 catecholamines - 10-30 s. The main part of catecholamines is rapidly metabolized in various tissues with the participation of specific enzymes (see section 9). Only a small portion of adrenaline (~5%) is excreted in the urine.

2. Mechanism of action and biological functions of catecholamines

Catecholamines act on target cells through receptors localized in the plasma membrane. There are 2 main classes of such receptors: α-adrenergic and β-adrenergic. All catecholamine receptors are glycoproteins that are products of different genes, differ in affinity for agonists and antagonists, and transmit signals to cells using different second messengers. This determines the nature of their influence on the metabolism of target cells.

Rice. 11-22. Synthesis and secretion of catecholamines. The biosynthesis of catecholamines occurs in the cytoplasm and granules of cells of the adrenal medulla. Some granules contain adrenaline, others norepinephrine, and some contain both hormones. When stimulated, the contents of the granules are released into the extracellular fluid. A - adrenaline; NA - norepinephrine.

Epinephrine interacts with both α- and β-receptors; norepinephrine at physiological concentrations primarily interacts with α-receptors.

The interaction of the hormone with β-receptors activates adenylate cyclase, while binding to the α 2 receptor inhibits it. When the hormone interacts with the α 1 receptor, phospholipase C is activated and the inositol phosphate signal transduction pathway is stimulated (see section 5).

The biological effects of adrenaline and norepinephrine affect almost all body functions and are discussed in the appropriate sections. What all these effects have in common is the stimulation of processes necessary for the body to withstand emergency situations.

3. Pathology of the adrenal medulla

The main pathology of the adrenal medulla is pheochromocytoma, a tumor formed by chromaffin cells and producing catecholamines. Clinically, pheochromocytoma is manifested by repeated attacks of headache, palpitations, sweating, increased blood pressure and is accompanied by characteristic changes in metabolism (see sections 7.8).

G. Hormones of the pancreas and gastrointestinal tract TRACT

The pancreas performs two important functions in the body: exocrine and endocrine. The exocrine function ensures the synthesis and secretion of enzymes and ions necessary for digestive processes. The endocrine function is performed by the cells of the islet apparatus of the pancreas, which secrete hormones involved in the regulation of many processes in the body.

In the islet part of the pancreas (islets of Langerhans), there are 4 types of cells that secrete different hormones: A- (or α-) cells secrete glucagon, B- (or β-) - insulin, D- (or δ-) - somatostatin, F -cells secrete pancreatic polypeptide.

Only a very small portion of adrenaline (less than 5%) is excreted in the urine. Catecholamines quickly

Rice. 49.2. Scheme of catecholamine biosynthesis. TG-tyrosine hydroxylase; DD-DOPA decarboxylase; FNMT - phenylganolamine-GM-methyltransferase; DBH-dopamine-R-hydroxylase; ATP-adenosine triphosphate. The biosynthesis of catecholamines occurs in the cytoplasm and in various granules of cells of the adrenal medulla. Some granules contain epinephrine (A), others contain norepinephrine (NA), and some contain both hormones. Upon stimulation, the entire contents of the granules are released into the extracellular fluid (ECF).

metabolized by catechol-O-methyltransferase and monoamine oxidase to form inactive O-methylated and deaminated products (Fig. 49.3). Most catecholamines serve as substrates for both of these enzymes, and these reactions can occur in any sequence.

Catechol-O-methyltransferase (COMT) is a cytosolic enzyme found in many tissues. It catalyzes the addition of a methyl group, usually at the third position (meta position) of the benzene ring of various catecholamines. The reaction requires the presence of a divalent cation and S-adenosylmethionine as a methyl group donor. As a result of this reaction, depending on the substrate used, homovanillic acid, normetanephrine and metanephrine are formed.

Monoamine oxidase (MAO) is an oxidoreductase that deaminates monoamines. It is found in many tissues, but in the highest concentrations - in the liver, stomach, kidneys and intestines. At least two MAO isoenzymes have been described: MAO-A nerve tissue, deaminating serotonin, adrenaline and norepinephrine, and MAO-B in other (non-nervous) tissues, most active against -phenylethylamine and benzylamine. Dopamine and tyramine are metabolized in both forms. The question of the connection between affective disorders and an increase or decrease in the activity of these isoenzymes. MAO inhibitors have found use in the treatment of hypertension and depression, but the ability of these compounds to enter into reactions that are dangerous to the body with those contained in food and medicines sympathomimetic amines reduces their value.

O-Methoxylated derivatives undergo further modification by forming conjugates with glucuronic or sulfuric acid.

Catecholamines form many metabolites. Two classes of such metabolites are used diagnostically because they are present in urine in easily measurable quantities. Metanephrines are methoxy derivatives of epinephrine and norepinephrine; The O-methylated deaminated product of epinephrine and norepinephrine is 3-methoxy-4-hydroxymandelic acid (also called vanillylmandelic acid, VMA) (Fig. 49.3). With pheochromocytoma, the concentration of matanephrines or VMC in the urine is increased in more than 95% of patients. Diagnostic tests based on the determination of these metabolites differ high accuracy, especially when used in combination with the determination of catecholamines in urine or plasma.