HISTAMINE (beta imidazoline - 4(5) - ethylamine) — biogenic, physiologically active heterocyclic amine, C 5 H 9 N 3 ; participates in implementation of allergic reactions as a mediator, it is used as medicine. Constitutional formula:
It is synthesized in 1907 from imidazolpropionovy to - you by A. Vindaus and W. Voght. In 1909 Dale and P. Laidlaw removed a histamine from an ergot.
And animal G. in insignificant quantities (less than 5%) comes to a human body with food (e.g., milk supports him 0,5 mkg/ml, meat — 0,5 mkg/g, bread — 0,1 mkg/g). Part G. is formed in intestines from histidine (see) under the influence of a bacterial histidinedecarboxylase (KF 4. 1. 1. 22). Excess receipt of a histidine with food (e.g., at preferential meat diet) activates a bacterial histidinedecarboxylase. Surplus formed at this G. is removed with urine. The histamine which is formed in intestines call exogenous (see the scheme).
The most part of G. is synthesized in cells of an organism by decarboxylation of a histidine by a fabric histidinedecarboxylase. Its coenzyme is piridoksal-5' - phosphate, strong inhibitor — an alpha methylhistidine., formed in cells, call an endogenous histamine.
Almost all human organs and animals support G. Kolichestvo it strongly varies in different fabrics and at different types of animals: in easy monkeys to 100 mkg/g, in skin of the person apprx. 30 mkg/g (A. D. Ado, 1970). In most of all G.'s brain find in a hypothalamus and a hypophysis. It is not enough in a thalamus, an oblong and spinal cord. The ground mass of G. in fabrics is in an inactive state in the form of labile complexes with proteins, heparin, sulfate polysaccharides, nucleinic to-tami, phosphatides. Distinguish two forms of deposition of the connected G. Pervaya — deposition in mast cells of connecting fabric where G.'s communication with a proteinaceous and heparin complex is rather steady and release it happens under the influence of certain substances, so-called liberator. The second form — deposition in the fabrics poor in mast cells, in cells of the body, napr, in lungs, sialadens, a mucous membrane of a stomach. These bodies usually have high gistaminoobrazuyushchy ability, and G. is released from cells under influence fiziol, incentives, napr, under the influence of irritation of cholinergic nerve fibrils. In blood G. it is preferential connected with granules of basophiles and eosinophils, part G. can form a complex with gamma-globulins. Small amounts of G. reside in blood and others biol, liquids In a stand-at-ease. Free G.'s maintenance in whole blood of healthy people fluctuates, according to different authors, from 20 to 100 ng/ml, and in plasma from 0 to 5 ng/ml. At various patol, processes free G.'s maintenance in blood can sharply increase. However high pharmakol, free G.'s activities counteract mechanisms of its destruction in an organism and removal of its metabolites with urine (see the scheme).
The main ways of an inactivation of G. in an organism are oxidizing deamination by means of the pyridoxaleft enzyme of a histaminase (see. Diaminoksidaza ) with education imidazoluksusny to - you and a riboside imidazoluksusny to - you and methylation of an imidazolny ring of G. with the help a histamine methyltransferase (KF 2. 1. 1. 8). Marked a histamine is the main metabolite of G. at many animal species and the person. A part of an educated methylhistamine is removed directly with urine, a part is oxidized monoamine oxidase (KF 1. 4. 3. 4) also it is removed in the form of 1-methylimidazole-4-acetum to - you. The way of neutralization of G. in tissues of a brain is same. G.'s neutralization can be carried out also by means of acetylation, a cut happens with the participation of the acetylating factor most likely being KOA. This way of neutralization of G. is not of great importance in tissues of hematothermal animals, G.'s acetylation happens, generally in intestines under the influence of an indestinal flora; formed atsetilgistamin it is removed with urine.
Fiziol, G.'s role is not absolutely clear and continues to be studied. G.'s action is shown on site its educations and release. Fiziol, most has activity the endogenous G. which is formed out of mast cells [on Shayer's terminology (R. Schayer, 1968), «U-00BB\G. induced \]. In went. - kish. a path, according to Brody (V. of Brodie, 1966), G. plays a role of the humoral intermediary in secretion of slime, digestive enzymes and salt to - you. A. M. Chernukh established G.'s role in regulation of microcirculation and maintenance of a homeostasis. Participates in transfer of nervous impulse. There are data on G.'s participation in regulation of processes of growth (embryonic growth, an angenesis).
The histamine as a mediator of allergic reactions
G. participates in implementation patokhimichesky and patofiziol. stages of allergic reactions.
Increase in maintenance of free G. in blood and a lymph of a chest channel at an acute anaphylaxis was shown for the first time Feldberg (W. Feldberg, 1932) also by Dragstedt (S. of Dragstedt, 1932). Since then this fact is confirmed by numerous experiments and a wedge, researches and became the main proof of the so-called histamine theory anaphylaxis (see) and allergies (see). This theory was spoken well also by the following facts: entered by an animal from the outside, causes the state similar to an acute anaphylaxis renders the same action, as well as offending allergen on the isolated smooth muscle bodies of animals (a small bowel, a horn of a uterus, tissue of bronchial tubes), i.e. causes an anaphylactic contracture, to-ruyu G. antagonists remove; after transferring of an acute anaphylaxis in fabrics the number of the mast cells which are the main depots of the connected decreases.
At the same time there are also facts contradicting G.'s recognition as a universal mediator of an anaphylaxis. E.g., the shock arising at G.'s introduction to blood of animals is not always identical to anaphylactic; G. antagonists preventing development of histamine shock not always and not fully remove an acute anaphylaxis; at an acute anaphylaxis from fabrics not only G., but also other biologically active agents is released: heparin, serotonin, slowly reacting substance [Austin (To. F. Austen), 1974], kinina; some sensibilized fabrics (nervous, unstriated muscles) are excited by allergen directly, without G.'s participation as an intermediate link; histamine shock is not followed by desensitization of an animal to the subsequent introduction of G. as it is observed at an acute anaphylaxis; at an acute anaphylaxis coagulability of blood decreases, and G. raises it (A. D. Ado, 1970).
Thus, G. is not a universal mediator for all cases of an allergy, but plays a role important intermediate ’the Even at many allergic reactions. G.'s participation in the mechanism of some allergic diseases of the person (atopic and infectious and allergic bronchial asthma, a small tortoiseshell, a Quincke's edema, pollinoses, an allergic rinosinusit, a dermatosis etc.) which are followed by change of maintenance of G. in blood, change of activity of a histaminase and other enzymes, destroying G. and G.'s emergence and its metabolites in urine in quantity, bigger against norm is known [E. E. Rajka, 1966; I. L. Vaysfeld, 1969; T. S. Sokolova, 1971].
G.'s role in reactions at an allergy of the slowed-down type is not clear. However Schild (H. Lake of Schild, 1967), H. D. Beklemishev (1968), etc. find possible G.'s participation in some of its manifestations, napr, in tuberkulinovy reaction and contact dermatitis. Fluctuations of maintenance of the connected G. in fabrics and strengthening of gistaminoobrazuyushchy ability of skin are found. But these phenomena are short-term and are found preferential in early terms when cellular and fabric reactions did not manage to be developed yet. Shayer (1963) considers that strengthening of education of G. at the slowed-down allergy results from action the histidine dekarboksit elements, providing emergence of the so-called «induced» G. (on Shayer's terminology), action to-rogo is directed to regulation of microcirculation and maintenance thus in fabrics of necessary amount of blood.
Increase in maintenance of G. in sensibilized fabrics due to strengthening of its education from a histidine is well known also in reactions of an immediate allergy [G. Kahlson and soavt., 1964]. Gistaminoobrazuyushchy ability in sensibilized fabrics in comparison with normal increases with various intensity and speed. In lungs, a liver and skin at most of G.'s education it is observed in 3 — 6 hours after effect of allergen, in a spleen and intestines — in 24 hours and more. G.'s education can be continued many hours, and even days. The number of the formed G. does not depend on a saturation of body mast cells. In an aorta where they are not enough, G. is formed so intensively, as well as in skin where there is a lot of mast cells.
The new formed G. physiologically labilen, is easily released from the place of education and it is found in liquids of an organism. Metabolites it are removed with urine.
Other source of free G. in fluid mediums of an organism is its release from the connected state in mast cells of connecting fabric and basophiles of blood with whom the most part of stocks of G. of an organism is deposited. Mast cells, e.g., it contain 20 — 30 mkg on 106 cells; from mast cells and G.'s basophiles it is released under the influence of liberator. Patton (W. Paton, 1958), B. Alpern (1973) G.'s liberator divide into two groups: low-molecular substances (monoamines, diamines, diamidines, the replaced arylamines, ammonium, d-tubocurarine, morphine, etc.) and high-molecular (dextrans, ovomucoids, peptones, polyvinylpyrrolidine, substance 48/80, Twin-20, polymyxin, proteolytic enzymes, poisons and toxins, complexes antigen — an antibody). Many proteins, including serum proteins have properties of liberator.
At action of liberator on cells there is an emission of granules (single or masses) from a cell (degranulation) and escaping them G. and other biologically active agents (heparin, serotonin, proteases).
On the mechanism of action G.'s liberator divide [D. R. Stanworth, 1974] on not selective (cytotoxic) agents, napr, octylamine, decylamine, Chlorpromazinum, the Triton of H-100, melitin, and selective (not cytotoxic) agents, napr, substance 48/80, a complex antigen — an antibody, some polypeptides with the main properties and so forth. Substances of the second group cause G.'s release without destruction of mast cells. Points lack of an ionic yield of K+ and extra granular cytoplasmic inclusions to it (ATP, lactate dehydrogenases) from mast cells at the release from them of G. caused by a specific antigen and also preservation of membrane potential of mast cells and lack of receipt in cytoplasm out of limits of a cytoplasmic membrane and perigranulyarny membranes of extracellular markers (hemoglobin and lanthanum).
Many liberator of G. represent connections with properties of the bases. Consider (D. R. Stanworth, 1974) that if situation and alternation of the main groups in a molecule of a liberator corresponds to situation and alternation of free groups with acid properties (carboxyl groups) on a membrane of a mast cell, then it leads to their interaction, as is the push activating a cell. In that site of a Fc-fragment of a molecule of an antibody which opens after connection with antigen and which is related to activation of a cell the sequence of the amino-acid remains with the main properties is similar to the sequence of the main groups in other liberator of.
G.'s release caused by not cytotoxic liberator is the active (energetically dependent) process proceeding with the energy consumption provided to ATP which is formed in mast cells for the account of both aerobic, and anaerobic ways of energy balance. Therefore exhaustion of reserves of ATP and the braking of release of G. connected with it can be reached on condition of simultaneous inhibition of breath and glycolysis. About 20% of total quantity of ATP in mast cells are spent for G.'s release [Diamond (V. of Diamant), 1975]. Specific ways of use of ATP for G.'s release are still unknown. Consider that ATP is spent for ensuring advance of granules on system of microtubules to a cellular surface. However there are no direct proofs of existence in mast cells of this system.
The initial stage of activation of mast cells the complex which is formed on their surface antigen — the antibody is activation cellular serine-esterases with the participation of ions of Sa 2+ . G.'s release caused by antigen depends on system cyclic 3', 5 '-adenosinemonophosphate (tsAMF): increase in its contents in cells brakes, and decrease strengthens release G. Rol tsAMF is not universal in all types of not cytotoxic release of G.: substance 48/80 releases G., circumventing the tsAMF system [Fredkholm (V. of Fredholm) and soavt., 1976].
Ions Ca 2+ are necessary for activation not only initial, but also later stages of reaction, the following behind energetically dependent stage and the granules consisting in advance to a cellular membrane and in their conclusion out of limits of a cell (process of degranulation).
Increase in permeability of the general cytoplasmic membrane and the perigranulyarny membranes merging with it leads to receipt in the spaces surrounding granules, extracellular ions. Extracellular cations, hl. obr. ions of Na + , force out G. from the granular matrix representing the heparin and proteinaceous complex having properties of weak cation exchanger (B. U brought, 1970). Thus, G. is released not only from the granules which left a cell but also from the granules remaining within a cell, to the Crimea there was an access of extracellular cations. By what in the way (cytotoxic or not cytotoxic) receipt of extracellular cations in perigranulyarny spaces was not caused, G.'s removal from a granular matrix is carried out the same — on the mechanism of cation-exchange process.
The mechanism of release of G. from basophiles caused by a specific antigen or allergen is essentially similar to the mechanism of its release from mast cells. This process can be considered as active reaction of living cells to a specific irritant. For providing an exit of G. from sensibilized leukocytes of the person it is enough to add only several pikogramm (10 - 12 d) the corresponding allergen that testifies to high immune specificity of this reaction.
The free G. released from granules of mast cells or neogenic in other fabrics, getting into fluid mediums of an organism, causes the general and local reactions. The most typically general reaction is shown in a collapse, or in the «histamine shock» arising at insufficiency of mechanisms of neutralization of free G. Harakternymi for an allergy forms of local reaction to G. the bronchospasm and the skin reaction described as «triple response» or «the triple answer» of Lewis (1924) are: 1) local trichangiectasia and emergence of redness; 2) distribution of an erythema as a result of expansion of the next arterioles; 3) formation of a blister owing to increase in permeability of vessels of skin. the 1st and 3rd phases of reaction are caused by direct action of G. on capillaries, the 2nd phase is caused by action of acetylcholine which is allocated reflex at G.'s irritation of touch fibers of back roots of a spinal cord.
A wedge, the displays of an allergy caused by release from fabrics G. can be to some extent reduced by introduction of antagonists of G. (see. Antihistaminic substances ). The mechanism of their action is various: they can slow down G.'s release from cells, block gistaminretseptor on a surface of effector cells or possess competitive action in relation to G. See also Mediators of allergic reactions .
Histamine as drug
Histamini dihydrochloridum; synonym: Eramin, Ergamine, Histalgine, Histodol, Istal, Peremin.
Is issued in the form of crystal G. of phosphate or dihydrochloride. Let's well dissolve in water. On site G.'s introductions there is a reddening caused by a trichangiectasia and the papule as a result of increase in permeability of capillaries and hypostasis of fabrics is formed; there is a feeling of an itch, pain caused by irritation of the terminations of sensory nerves.
At introduction of per os G. maloaktiven since collapses a histaminase went. - kish. path. At parenteral administration of G. specifically stimulates function of secretory cells of digestive, bronchial, lacrimal glands and strengthens department of bile. Especially strongly G. increases formation of a gastric juice, being a powerful stimulator of secretory activity of the obkladochny cells of a stomach allocating salt to - that. Raises a tone (up to a spasm) and strengthens reductions of muscles of bronchial tubes and a small intestine. And at the person G. causes decrease in the ABP as a result of a trichangiectasia in the majority of animals, increase in their permeability and as the investigations of it, a degrowth of the circulating blood. The trichangiectasia is result of the paralysis of precapillary sphincters caused by G. G.'s action is connected with its influence on gistaminchuvstvitelny receptors of cells. Causes also a delay of blood in veins of a liver and lungs with reduction of inflow of blood to the right or left heart owing to what the amount of the circulating blood also decreases.
G.'s clinic applies to diagnosis pheochromocytomas (see): intravenous administration of 0,025 — 0,05 mg of G. in 1 — 5 min. causes in patients short-term increase in the ABP on 40/25 mm of mercury., followed by strengthening of adrenaline in blood. Causes a similar phenomenon in a part of healthy faces of G.
Histamine test is carried out in the preoperative period for definition of a condition of blood circulation and secretory ability of gastric glands.
As medicine G. has limited use. Sometimes use at polyarthritises, joint and muscular rheumatism: intradermal administration of dihydrochloride or phosphate G. (0,1 — 0,5 ml of 0,1% of solution), rubbing in of the ointments containing G. and G.'s electrophoresis cause a strong hyperemia and reduction of morbidity; at the pains connected with damage of nerves at radiculitises, plexites, etc., at the same time the drug is administered vnutrikozhno (0,2 — 0,3 ml of 0,1% of solution). G.'s use is contraindicated at periods, quinsy, feverish states. At overdose the collapse (histamine shock) is possible.
Form of release: the ampoules containing G. from 0,01 to 10 mkg and from 15 to 50 mkg.
The test of specific release of a histamine
the Method of identification of a specific sensitization of an organism is based on release of a histamine from leukocytes of blood of the patient after addition to them of offending allergen.
The test is used with the research purposes for identification of an atopic sensitization (see. Atopy ), at pollinoses (see), food allergy (see) and medicinal allergy (see), and also for control of efficiency of specific desensitization (see. Desensitization ). It is offered in 1964 by L. Likhtenstayn and A. G. Osier. An essential lack of a method — use of large volume of blood (100 ml). In 1970 May (Ch. D. May) with sotr. changed a method a little that allowed to reduce the volume of blood to 10 ml.
IgE-antibodies, collecting in blood of patients with atopic diseases, hl are fixed. obr. on basophiles, to-rye contain the most part of a histamine of blood. The fixed IgE-antibodies perform function of a receptor for offending allergen, causing the phenomenon of a sensitization. As a result of reaction allergen — an antibody from basophiles mediators, including and a histamine are released (see. Mediators of allergic reactions ). T, the lake, by this test it is possible to judge indirectly presence on a surface of leukocytes of the cellular fixed IgE-antibodies and degree of order of the patient to this allergen. It is of great importance in clinic of allergic diseases since one of origins of an atopic disease and its aggravation is increase in quantity of the cellular fixed IgE-antibodies.
The test includes three main stages: receiving the washed suspension of functional and active leukocytes from blood of patients, an incubation of suspension of leukocytes (within 1 hour at pH 7,35 and temperature 37 °) with various concentration of allergens and definition by a flyuorimetrichesky or isotope method of concentration of G. separately in nadosadochny liquid and in leukocytes. Extracts of the allergens used at the same time shall not contain phenol, to-ry possesses nonspecific gistaminvysvobozhdayushchy action. Besides, the crude extracts have nonspecific toxicity, and the use of high concentration of nek-ry extracts causes nonspecific release of G. from leukocytes. At the same time each studied antigen is ottitrovyvat on leukocytes of healthy donors. For this purpose use allergens in the decreasing cultivations. Allergens in the concentration which are not causing G.'s release can be used for the test with leukocytes of patients. As control on specificity add allergen to suspension of leukocytes, to Krom of the patient did not find a sensitization. Concentration of the released G. is expressed percentage of the general maintenance of G. in test.
At an incubation with offending allergen of leukocytes of patients with an atonic disease dozozavisimy release of is noted. At the same time distinguish cellular reactivity and cellular sensitivity. Understand the maximum release of G. depending on concentration of allergen as cellular reactivity. Cellular: sensitivity is expressed by amount of antigen, a cut it is necessary for release 50% of a histamine from mast cells.
The test is labor-consuming; introduction of an automatic method of definition of G., and also the use of whole blood instead of suspension of leukocytes will allow to simplify considerably this test and to make it more available for a wedge, laboratories.
Bibliography: Ado A. D. General allergology, M., 1970, bibliogr.; Alpern B. An allergy, the lane with fr., M., 1973; Gushchin I. S. Anaphylaxis of smooth and cardiac muscles, M., 1973, bibliogr.; Degli S. and Nikolson. Metabolic ways, the lane with English, page 218, M., 1973; Uspensky V. I. Gistamin, M., 1963, bibliogr.; Chernukh A. M. and Timkina M. I. Dinamika of bioelectric activity of terminal vessels of a mesentery of a small intestine of a rat under the influence of a histamine, the Stalemate. fiziol, and Eksperim, rubbed., t. 15, JSIa 3, page 49, 1971, bibliogr.; Goldstein D., Aronow L. and. To a lma'n S. M of Principles of drug action, basis of pharmacology, N. Y., 1974; G of u n J. P. Histamine, in book Handbook neurochem., ed. by A. Lajtha, v. 4, N. Y., 1970, bibliogr.; Histamine and antihistamines, ed.byZ. M. Bacq a. o., Oxford — N.Y., 1973; Kaliner M. a. Austen K.F. The hormonal control of the immunologic release of histamine and slow reating substance of anaphylaxis from human lung, in book; Cyclic nucleotides, immune responses a. tumor growths, ed. by W. Braun a. o., p. 128, N. Y., 1974; The pharmacological basis of therapeutics, ed. by L. S. Goodman a. A. Gilman, L., 1975; Stan wort h D.R. Immediate hypersensitivity, in book: North-Holland research monographs, Frontiers of biology, v. 28, p. 69, Amsterdam a. o., 1974; Tauber A. I. a, o. Immunologic release of histamine and slow reacting substance of anaphylaxis from human lung, J. Immunol., v. Ill, p. 27, 1973.; S. M eagles. Release of a histamine of in vitro from leukocytes of peripheral blood of patients with a neysserialny form of bronchial asthma, Immunology, No. 1, page 90, 1980; S. M. and Shustov V. I. Eagles. The test of release of a histamine in diagnosis of a pollinosis, Klin, medical, t. 58, No. 1, page 88, 1980; Lichtenstein L. M of a. Osier A. G. Studies on the mechanisms of hypersensitivity phenomena, J. exp. Med., v. 120, p. 507, 1964; May Ch. o. Procedures for immunochemical study of histamine release from leukocytes with small volume of blood, J. Allergy, v. 46, p. 12, 1970.
L. M. Ishimova; I. V. Komissarov (pharm.), S. M. Orlov