Physiological role of catecholamines. Effect on secretion

Some human hormones and connection endocrine system with the nervous system are shown in Fig. 13.2. under direct control nervous system are the adrenal medulla and the hypothalamus; other endocrine glands connected with the nervous system indirectly, through the hormones of the hypothalamus and pituitary gland. In the cells of the hypothalamus, special peptides are synthesized - liberins (releasing hormones). In response to the excitation of certain centers of the brain, 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, statins are produced in the hypothalamus, which inhibit the synthesis and secretion of pituitary hormones.

central nervous system

N erv e connections

N erv e ties ___
	Hypothalamus		Antidiure-
			tic
			Oxytocype		uterine muscles,
					mammary glands
			Melanocyte-
			stimulate-		melanocytes
			ing hormone
			Prolactia		Mammary gland
Somatotropin
			Lutsinizi-		Folliculo-
	Corticotropin	Thyrotropin		stimulating
Brain		Thyroid			testicles
substance
	adrenal glands
adrenal glands
ADRENALIN	CORTISOL	THIROXINE ESTROGEN			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 polyfunctional. For example, epinephrine and noradrenaline regulate not only carbohydrate and fat metabolism, but also heart rate, smooth muscle contraction, blood pressure. In particular, for this reason, many hormones, especially paracrine ones, cannot be classified according to biological functions.

Changes in the concentration of hormones in the blood

The concentration of hormones in the blood is low, of the order of IO6-IO JJ mol / l. The 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 an appropriate stimulus depends on an increase in the rate of hormone synthesis 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 secreted into the blood with the participation of special mechanisms of secretion. These hormones after their synthesis are included in the secretory granules - membrane vesicles formed in the lamellar complex; the hormone os is released into the blood by the fusion of the granule with plasma membrane cells (exocytosis). The synthesis of hormones 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 quick response of the body to the action of a stimulus : the stimulus accelerates the fusion of the granules with the membrane and the release of the stored hormone into the blood.

Synthesis of steroid hormones

The structure and synthesis of many hormones are described in the previous sections. Steroid hormones are a group of compounds related in origin and structure: they are all formed from cholesterol. Intermediates in the synthesis steroid hormones pregnenolone and progesterone serve (Fig. 13.3). They are formed in all organs that synthesize any steroid hormones. Further 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 in 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 in 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 hyperproduction of steroid hormones, and decreases with hypoproduction.

Progesterone (C21) Aldosterone (C21)

Rice. 13.3. Ways of 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 of paracrine and autocrine action; in the blood in a physiologically active concentration, they practically do not exist (an exception is interleukin-1). Dozens of different cytokines are known. These include interleukins (lymphokines and monokines), interferons, peptide growth factors, colony stimulating factors. Cytokines are glycoproteins containing 100-200 amino acid residues. Most cytokines are produced and active in many cell types and respond to a variety of stimuli, including mechanical damage, viral infection, metabolic disorders and others. 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 to 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 response. Transforming growth factor (TGF-r) stimulates the synthesis and secretion of extracellular matrix components, cell growth and proliferation, and the synthesis of other cytokines.

Cytokines have overlapping yet distinct 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, 20:4 (5, 8, 11, 14), gives rise to a large group of paracrine hormones - eicosanoids. Arachidonic acid, supplied with food or 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 .. Further, 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 usually 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 various 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, smooth muscle relaxation and vasodilation (PGE2, also synthesized in most organs). PGI2 is synthesized mainly in the vascular endothelium, inhibits platelet aggregation, 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 ​​vessel damage (see Chapter 21). It, thromboxane TXA2, constricts blood vessels and bronchi, acting on smooth muscle cells (paracrine mechanism).

Eicosanoids act on target cells through specific membrane receptors. The binding of an eicosanoid to a receptor triggers the formation of a 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 long, and then it itself becomes pathological process disease and requires treatment. Inhibitors of eicosanoid synthesis are used to treat such conditions. Cortisol and its synthetic analogues (dexamethasone and others) induce the synthesis of lipocortin proteins, which inhibit phospholipase A2 (see Fig. 13.4). Aspirin (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 the chromaffin cells of the adrenal medulla. These cells got their name because they contain granules that stain red-brown under the action of potassium dichromate. Accumulations 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 at the nerve endings and reaches its targets in the blood.

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

Tyrosine - hydroxylase

Tyrosine is the direct precursor of catecholamines, and tyrosine hydroxylase limits the rate of the entire process of catecholamine biosynthesis. This enzyme occurs both in free form and in the form associated with 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 is also competitively inhibited by a number of tyrosine derivatives, including α-methyltyrosine. In some cases, this compound is used to block the excess production of catecholamines in pheochromocytoma, however, there are more effective agents that also have less pronounced side effect. Compounds of another group inhibit the activity of tyrosine hydroxylase by forming complexes with iron and thus removing the existing cofactor. An example of such a compound is α,-dipyridyl.

Catecholamines do not cross the blood-brain barrier and hence 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 violations of the synthesis of dopamine in the brain. dopamine precursor

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 as effective tool 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 α-DOPA to α-dihydroxyphenylethylamine (dopamine). The reaction is competitively inhibited by compounds resembling α-DOPA, such as a-methyl-DOPA. Halogenated compounds form a Schiff base with α-DOPA and also inhibit the decarboxylation reaction.

α-methyl-DOPA and other related compounds such as α-hydroxytyramine (derived from tyramine), α-methyl irosin and metaraminol have been successfully used to treat some forms of hypertension. The antihypertensive effect of these metabolites is apparently due to their ability to stimulate a-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) - oxidase with mixed function catalyzes the conversion of dopamine to norepinephrine. DBG uses ascorbate as an electron donor and fumarate as a modulator; the active center of the enzyme contains copper. DBH cells of the adrenal medulla are probably localized in secretory granules. Thus, the conversion of dopamine to norepinephrine occurs in these organelles. DBH is released from the cells of the adrenal medulla and nerve endings together with norepinephrine, but (unlike the latter) is not subjected to reuptake by nerve endings.

Phenylethanolamine-N-methyltransferase

Soluble enzyme phenylethanolamine - α-methyltransferase (FCMT) catalyzes β-methylation of norepinephrine with the formation of adrenaline in adrenaline-producing cells of the adrenal medulla. Since this enzyme is soluble, it can be assumed that the conversion of noradrenaline to adrenaline occurs in the cytoplasm. Synthesis of FIMT 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, apparently, is necessary for the induction

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

The sequence of catecholamine synthesis is quite simple: tyrosine -> dihydroxyphenylalanine (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 formation of adrenaline, in the endings of 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 that the synthesis of catecholamines can be modified by changing the activity of this enzyme as well. Some neurons lack the enzymes for the further conversion of dopamine, and it is he who is the final product. Other tissues contain dopamine-β-hydroxylase (cofactors - copper, ascorbic acid and oxygen), which converts dopamine to 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 that enter the medulla from the cortex through the portal venous system. This, perhaps, lies the explanation for the fact of combining 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, whereas adrenaline-producing cells receive blood mainly from venous sinuses located in the adrenal cortex.

The breakdown of catecholamines proceeds mainly under the influence of two enzyme systems: catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The main pathways for the breakdown of epinephrine and norepinephrine are schematically shown in Fig. 54. Under the action of COMT in the presence of a donor of methyl groups S-adrenosylmethionine, catecholamines are converted into normetanephrine and metanephrine (3-O-methyl derivatives of norepinephrine and adrenaline), which, under the influence of MAO, are converted into aldehydes and further (in the presence of aldehyde oxidase) into vanillylmandelic acid ( VMK) - 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-dioximandelic aldehyde, and then, under the influence of aldehyde oxidase and COMT, into 3,4-dioximandelic acid and HMA. In the presence of alcohol dehydrogenase, catecholamines can form 3-methoxy-4-hydroxyphenyl glycol, which is the main end product of the degradation of adrenaline and noradrenaline in the CNS.

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 the 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 the catecholamine molecule is also postulated, which can lead to the formation of intermediate products with pronounced biological activity.

Formed under the action of cytosolic enzymes, norepinephrine and adrenaline 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 capture of catecholamines by granules requires energy costs. In the chromaffin granules of the adrenal medulla, catecholamines are strongly associated with ATP (4:1 ratio) and specific proteins, chromogranins, which prevents the diffusion of hormones from the granules into the cytoplasm. The direct stimulus to the secretion of catecholamines is, apparently, the penetration of calcium into the cell, which stimulates exocytosis (fusion of the granule membrane with cell surface and their rupture with a complete release of soluble contents - catecholamines, dopamine-p-hydroxylase, ATP and chromogranins - into the extracellular fluid).

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

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

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

In blood plasma, catecholamines form an unstable complex with albumin. Adrenaline is transported primarily to the liver and skeletal muscles. Norepinephrine is formed mainly in organs innervated by sympathetic nerves (80% of the total). Norepinephrine reaches the peripheral tissues only in small amounts. 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 epinephrine (~5%) is excreted in the urine.

2. Mechanism of action and biological functions of catecholamines

Catecholamines act on target cells through receptors located 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 the cells of the adrenal medulla. Some granules contain adrenaline, others contain norepinephrine, and some contain both hormones. Upon stimulation, the contents of the granules are released into the extracellular fluid. A - adrenaline; NA - norepinephrine.

Adrenaline interacts with both α- and β-receptors; norepinephrine in physiological concentrations mainly 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 signaling pathway is stimulated (see Section 5).

The biological effects of epinephrine and norepinephrine affect almost all body functions and are discussed in the relevant sections. What all these effects have in common is the stimulation of the 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 recurrent 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

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 the digestive process. 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), 4 types of cells secrete different hormones: A- (or α-) cells secrete glucagon, B- (or β-) - insulin, D- (or δ-) - somatostatin, F -cells secrete a pancreatic polypeptide.

Only a very small part of adrenaline (less than 5%) is excreted in the urine. catecholamines fast

Rice. 49.2. Scheme of biosynthesis of catecholamines. TG-tyrosine hydroxylase; DD-DOPA decarboxylase; FNMT - phenyltganolamine-GM-methyltransferase; DBH-dopamine-P-hydroxylase; ATP-adenosine triphosphate. The biosynthesis of catecholamines occurs in the cytoplasm and in various granules of the 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 under the action of catechol-O-methyltransferase and monoamine oxidase with the formation of 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 nervous tissue, deamining serotonin, adrenaline and norepinephrine, and MAO-B in other (non-nervous) tissues, the most active in relation to -phenylethylamine and benzylamine. Dopamine and tyramine are metabolized by both forms. The question of the relationship between affective disorders and an increase or decrease in the activity of these isoenzymes. MAO inhibitors have found application in the treatment of hypertension and depression, however, the ability of these compounds to enter into reactions dangerous for the body with 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 in diagnostics because they are present in the urine in easily measurable amounts. Metanephrines are methoxy derivatives of adrenaline and norepinephrine; The O-methylated deaminated product of epinephrine and norepinephrine is 3-methoxy-4-hydroxymandelic acid (also called vanillylmandelic acid, VMA) (Figure 49.3). With pheochromocytoma, the concentration of matanephrines or VMK in the urine is increased in more than 95% of patients. Diagnostic tests based on the detection of these metabolites differ high precision, especially when used in conjunction with urinary or plasma catecholamine determinations.