Differential effects of Pistacia vera extracts on experimental atherosclerosis in a rabbit animal model: an experimental study. Experimental models Experimental models of atherosclerosis in vivo

The original meaning of the concept "atherosclerosis", proposed by Marchand in 1904, came down to only two types of changes: the accumulation of fatty substances in the form of mushy masses in the inner lining of the arteries (from the Greek athere - porridge) and sclerosis itself - a connective tissue thickening of the artery wall (from the Greek scleras - hard). The modern interpretation of atherosclerosis is much broader and includes ... “various combinations of changes in the intima of the arteries, manifested in the form of focal deposition of lipids, complex carbohydrate compounds, blood elements and products circulating in it, the formation connective tissue and calcium deposits" (WHO definition).

Sclerotically changed vessels (the most common localization is the aorta, arteries of the heart, brain, lower extremities) differ increased density and fragility. Due to a decrease in elastic properties, they are not able to adequately change their lumen depending on the need of an organ or tissue for blood supply.

Initially, the functional inferiority of sclerotically altered vessels, and, consequently, organs and tissues, is detected only when increased demands are placed on them, i.e., when the load increases. Further progression of the atherosclerotic process can lead to decreased performance even at rest.

A strong degree of atherosclerotic process, as a rule, is accompanied by a narrowing and even complete closure of the lumen of the arteries. With the slow sclerosis of arteries in organs with impaired blood supply, atrophic changes occur with the gradual replacement of functionally active parenchyma by connective tissue.

Rapid narrowing or complete closure of the lumen of the artery (in the case of thrombosis, thromboembolism or hemorrhage into the plaque) leads to necrosis of the organ area with impaired blood circulation, i.e. to a heart attack. Myocardial infarction is the most common and most dangerous complication of atherosclerosis of the coronary arteries.

Experimental models. In 1912, N. N. Anichkov and S. S. Khalatov proposed a method for modeling atherosclerosis in rabbits by introducing cholesterol inside (through a tube or by mixing it with regular food). Pronounced atherosclerotic changes developed after several months with daily use of 0.5 - 0.1 g of cholesterol per 1 kg of body weight. As a rule, they were accompanied by an increase in the level of cholesterol in the blood serum (3-5 times compared to the initial level), which was the basis for the assumption of a leading pathogenetic role in the development of atherosclerosis hypercholesterolemia. This model is easily reproducible not only in rabbits, but also in chickens, pigeons, monkeys, and pigs.

In dogs and rats resistant to cholesterol, atherosclerosis is reproduced by the combined effect of cholesterol and methylthiouracil, which suppresses thyroid function. This combination of two factors (exogenous and endogenous) leads to prolonged and severe hypercholesterolemia (over 26 mmol/l - 100 mg%). Addition to food butter and bile salts also contributes to the development of atherosclerosis.

In chickens (roosters), experimental atherosclerosis of the aorta develops after long-term (4 - 5 months) exposure to diethylstilbestrol. In this case, atherosclerotic changes appear against the background of endogenous hypercholesterolemia resulting from a violation hormonal regulation metabolism.

Etiology. The given experimental examples, as well as observations of spontaneous human atherosclerosis and its epidemiology, indicate that this pathological process develops as a result of the combined action of a number of factors (environmental, genetic, nutritional). In each individual case, one of them comes to the fore. There are factors that cause atherosclerosis and factors that contribute to its development.

On rice. 19.12 a list of the main etiological factors(risk factors) of atherogenesis. Some of them (heredity, gender, age) are endogenous. They manifest their effect from the moment of birth (gender, heredity) or at a certain stage of postnatal ontogenesis (age). Other factors are exogenous. The human body encounters their effects at various age periods.

The role of hereditary factors in the occurrence of atherosclerosis is confirmed by statistical data on high frequency coronary disease hearts in individual families, as well as in identical twins. We are talking about hereditary forms of hyperlipoproteinemia, genetic abnormalities of cellular receptors for lipoproteins.

Floor. At the age of 40 - 80 years, men suffer from atherosclerosis and myocardial infarction of an atherosclerotic nature more often than women (on average 3 - 4 times). After 70 years, the incidence of atherosclerosis among men and women is approximately the same. This indicates that the incidence of atherosclerosis among women occurs at a later period. These differences are associated, on the one hand, with a lower initial level of cholesterol and its content mainly in the fraction of non-atherogenic a-lipoproteins in the blood serum of women, and on the other, with the anti-sclerotic effect of female sex hormones. A decrease in the function of the gonads due to age or for any other reason (removal of the ovaries, their irradiation) causes an increase in serum cholesterol levels and a sharp progression of atherosclerosis.

It is assumed that the protective effect of estrogens comes down not only to the regulation of cholesterol levels in the blood serum, but also other types of metabolism in arterial wall, in particular oxidative. This anti-sclerotic effect of estrogens manifests itself mainly in relation to the coronary vessels.

Age. A sharp increase in the frequency and severity of atherosclerotic vascular lesions due to age, especially noticeable after 30 years (see. rice. 19.12), gave rise to some researchers the idea that atherosclerosis is a function of age and is exclusively biological problem[Davydovsky I.V., 1966]. This explains the pessimistic attitude towards a practical solution to the problem in the future. Most researchers, however, are of the opinion that age-related and atherosclerotic changes in blood vessels are various shapes arteriosclerosis, especially in late stages their development, but age-related changes in blood vessels contribute to its development. The effect of age, which promotes atherosclerosis, manifests itself in the form of local structural, physicochemical and biochemical changes in the arterial wall and general metabolic disorders (hyperlipemia, hyperlipoproteinemia, hypercholesterolemia) and its regulation.

Excessive nutrition. Experimental studies by N. N. Anichkov and S. S. Khalatov suggested the importance of the etiological role in the occurrence of spontaneous atherosclerosis of excess nutrition, in particular, excess intake of dietary fats. The experience of countries with a high standard of living convincingly proves that the more energy needs are met through animal fats and cholesterol-containing foods, the higher the cholesterol level in the blood and the incidence of atherosclerosis. On the contrary, in countries where animal fats account for a small proportion energy value daily diet (about 10%), the incidence of atherosclerosis is low (Japan, China).

In accordance with the program developed in the USA, based on these facts, reducing fat intake from 40% of total calories to 30% by the year 2000 should reduce mortality from myocardial infarction by 20 - 25%.

Stress. The incidence of atherosclerosis is higher among people in “stressful professions,” that is, professions that require prolonged and severe nervous tension (doctors, teachers, professors, administrative staff, pilots, etc.).

In general, the incidence of atherosclerosis is higher among the urban population compared to the rural population. This can be explained by the fact that in conditions big city a person is more often exposed to neurogenic stress influences. Experiments confirm the possible role of neuropsychic stress in the occurrence of atherosclerosis. Combining a high-fat diet with nervous tension should be considered unfavorable.

Physical inactivity. Sedentary lifestyle, sharp decrease physical activity(hypodynamia), characteristic of humans in the second half of the 20th century, is another important factor atherogenesis. This position is supported by the lower incidence of atherosclerosis among manual workers and the higher incidence among people engaged in mental work; faster normalization of cholesterol levels in the blood serum after its excess intake from the outside under the influence of physical activity.

The experiment revealed pronounced atherosclerotic changes in the arteries of rabbits after placing them in special cages, which significantly reduced their motor activity. A particular atherogenic danger is the combination sedentary lifestyle life and excess nutrition.

Intoxication. The influence of alcohol, nicotine, intoxication of bacterial origin and intoxication caused by various chemicals (fluorides, CO, H 2 S, lead, benzene, mercury compounds) are also factors contributing to the development of atherosclerosis. In most of the intoxications examined, not only general disorders were noted fat metabolism, characteristic of atherosclerosis, but also typical dystrophic and infiltrative-proliferative changes in the arterial wall.

Arterial hypertension Apparently, it does not have independent significance as a risk factor. This is evidenced by the experience of countries (Japan, China), whose population is often sick hypertension and rarely - atherosclerosis. However, high blood pressure is becoming increasingly important as a contributing factor to the development of atherosclerosis.

factor in combination with others, especially if it exceeds 160/90 mm Hg. Art. Thus, at the same cholesterol level, the incidence of myocardial infarction with hypertension is five times higher than with normal blood pressure. In an experiment on rabbits whose food was supplemented with cholesterol, atherosclerotic changes develop faster and reach a greater extent against the background of hypertension.

Hormonal disorders, metabolic diseases. In some cases, atherosclerosis occurs against the background of previous hormonal disorders ( diabetes, myxedema, decreased function of the gonads) or metabolic diseases (gout, obesity, xanthomatosis, hereditary forms of hyperlipoproteinemia and hypercholesterolemia). The etiological role of hormonal disorders in the development of atherosclerosis is also evidenced by the above experiments on the experimental reproduction of this pathology in animals by influencing the endocrine glands.

Pathogenesis. Existing theories of the pathogenesis of atherosclerosis can be reduced to two, fundamentally different in their answers to the question: what is primary and what is secondary in atherosclerosis, in other words, what is the cause and what is the consequence - lipoidosis of the inner lining of the arteries or degenerative-proliferative changes in the latter. This question was first raised by R. Virchow (1856). He was the first to answer it, pointing out that “under all conditions, the process probably begins with a certain loosening of the connective tissue basic substance, of which the inner layer of the arteries mostly consists.”

Since then, the idea of the German school of pathologists and its followers in other countries began, according to which atherosclerosis initially develops dystrophic changes the inner lining of the artery wall, and the deposition of lipids and calcium salts is a secondary phenomenon. The advantage of this concept is that it is able to explain the development of spontaneous and experimental atherosclerosis, both in cases where there are pronounced violations cholesterol metabolism, and in their absence. The authors of this concept assign a primary role to the arterial wall, i.e., the substrate that is directly involved in the pathological process. “Atherosclerosis is not only and not so much a reflection of general metabolic changes (in the laboratory they can even be elusive), but rather a derivative of the own structural, physical and chemical transformations of the substrate of the arterial wall... The primary factor leading to atherosclerosis lies precisely in the arterial wall itself , in its structure and in its enzyme system" [Davydovsky I.V., 1966].

In contrast to these views, since the experiments of N.N. Anichkov and S.S. Khalatov, mainly thanks to the research of domestic and American authors, the concept of the role of common factors in the development of atherosclerosis has been successfully developed metabolic disorders in the body, accompanied by hypercholesterolemia, hyper- and dyslipoproteinemia. From this point of view, atherosclerosis is a consequence of the primary diffuse infiltration of lipids, in particular cholesterol, into the unchanged inner lining of the arteries. Further changes in the vascular wall (the phenomena of mucoid edema, dystrophic changes in the fibrous structures and cellular elements of the subendothelial layer, productive changes) develop due to the presence of lipids in it, i.e. they are secondary.

Initially, the leading role in increasing the level of lipids, especially cholesterol, in the blood was attributed to the nutritional factor (excessive nutrition), which gave the name to the corresponding theory of the occurrence of atherosclerosis - nutritional. However, very soon it had to be supplemented, since it became obvious that not all cases of atherosclerosis can be put in a causal relationship with nutritional hypercholesterolemia. According to combination theory N. N. Anichkova, in the development of atherosclerosis, in addition to the nutritional factor, endogenous disorders of lipid metabolism and its regulation, mechanical effects on the vessel wall, changes blood pressure, mainly its increase, as well as dystrophic changes in the arterial wall itself. In this combination of causes and mechanisms of atherogenesis, some (nutritional and/or endogenous hypercholesterolemia) play the role of an initial factor. Others either provide an increased supply of cholesterol into the vessel wall or reduce its excretion from it through the lymphatic vessels.

In the blood, cholesterol is contained in chylomicrons (fine particles not dissolved in plasma) and lipoproteins - supramolecular heterogeneous complexes of triglycerides, cholesterol esters (core), phospholipids, cholesterol and specific proteins (apoproteins: APO A, B, C, E), forming surface layer. There are certain differences between lipoproteins in size, core-to-shell ratio, qualitative composition and atherogenicity.

Four main fractions of blood plasma lipoproteins have been identified depending on density and electrophoretic mobility.

Noteworthy is the high protein content and low lipid content in the high-density lipoprotein fraction (HDL - α-lipoproteins) and, conversely, low content protein and high - lipids in the fractions of chylomicrons, very low-density lipoproteins (VLDL - pre-β-lipoproteins) and low-density lipoproteins (LDL - β-lipoproteins).

Thus, blood plasma lipoproteins deliver cholesterol and triglycerides synthesized and obtained from food to the places of their use and storage.

HDL has an antiatherogenic effect by reverse transport of cholesterol from cells, including from blood vessels, to the liver with subsequent excretion from the body in the form of bile acids. The remaining fractions of lipoproteins (especially LDL) are atherogenic, causing excessive accumulation of cholesterol in the vascular wall.

IN table 5 The classification of primary (genetically determined) and secondary (acquired) hyperlipoproteinemia with varying degrees of severity of atherogenic action is given. As follows from the table, the main role in the development of atheromatous changes in blood vessels is played by LDL and VLDL, their increased concentration in the blood, and excessive entry into the vascular intima.

Excessive transport of LDL and VLDL into the vascular wall results in endothelial damage.

In accordance with the concept of American researchers I. Goldstein and M. Brown, LDL and VLDL enter cells by interacting with specific receptors (APO B, E-glycoprotein receptors), after which they are endocytically captured and fused with lysosomes. In this case, LDL is broken down into proteins and cholesterol esters. Proteins are broken down into free amino acids, which leave the cell. Cholesterol esters undergo hydrolysis with the formation of free cholesterol, which enters the cytoplasm from lysosomes with subsequent use for various purposes (membrane formation, synthesis steroid hormones etc.). It is important that this cholesterol inhibits its synthesis from endogenous sources; in excess, it forms “reserves” in the form of cholesterol esters and fatty acids, but, most importantly, by mechanism feedback inhibits the synthesis of new receptors for atherogenic lipoproteins and their further entry into the cell. Along with the regulated receptor-mediated mechanism of LP transport, which provides the internal needs of cells for cholesterol, interendothelial transport is described, as well as the so-called unregulated endocytosis, which is transcellular, including transendothelial vesicular transport of LDL and VLDL with subsequent exocytosis (into the intima of arteries from the endothelium, macrophages, smooth muscle cells).

Taking into account the stated ideas mechanism of the initial stage of atherosclerosis, characterized by excessive accumulation of lipids in the intima of the arteries, may be caused by:

1. Genetic anomaly of receptor-mediated endocytosis of LDL (absence of receptors - less than 2% of the norm, a decrease in their number - 2 - 30% of the norm). The presence of such defects was found in familial hypercholesterolemia (type II A hyperbetalipoproteinemia) in homo- and heterozygotes. A line of rabbits (Watanabe) with a hereditary defect in LDL receptors was bred.

2. Overload of receptor-mediated endocytosis in alimentary hypercholesterolemia. In both cases, there is a sharp increase in the unregulated endocytotic uptake of drug particles by endothelial cells, macrophages and smooth muscle cells of the vascular wall due to severe hypercholesterolemia.

3. Slowing down the removal of atherogenic lipoproteins from the vascular wall through the lymphatic system due to hyperplasia, hypertension, and inflammatory changes.

A significant additional point is the various transformations (modifications) of lipoproteins in the blood and vascular wall. We are talking about the formation under conditions of hypercholesterolemia of autoimmune complexes of LP - IgG in the blood, soluble and insoluble complexes of LP with glycosaminoglycans, fibronectin, collagen and elastin in the vascular wall (A. N. Klimov, V. A. Nagornev).

Compared with native drugs, the uptake of modified drugs by intimal cells, primarily macrophages (via cholesterol-unregulated receptors), increases sharply. This is believed to be the reason for the transformation of macrophages into so-called foam cells, which form the morphological basis lipid stain stages and with further progression - atherom. The migration of blood macrophages into the intima is ensured by the monocyte chemotactic factor, formed under the influence of LP and interleukin-1, which is released from the monocytes themselves.

At the final stage, they are formed fibrous plaques as a response of smooth muscle cells, fibroblasts and macrophages to damage, stimulated by growth factors of platelets, endothelial cells and smooth muscle cells, as well as the stage of complicated lesions - calcification, thrombus formation and etc. ( rice. 19.13).

The above concepts of the pathogenesis of atherosclerosis have their own strong and weak sides. The most valuable advantage of the concept of general metabolic disorders in the body and primary lipoidosis of the arterial wall is the presence of an experimental cholesterol model. The concept of the primary significance of local changes in the arterial wall, despite the fact that it was expressed more than 100 years ago, does not yet have a convincing experimental model.

As can be seen from the above, in general they can complement each other.

In 1912, N. N. Anichkov and S. S. Khalatov proposed a method for modeling atherosclerosis in rabbits by introducing cholesterol inside (through a tube or by mixing it with regular food). Pronounced atherosclerotic changes developed after several months with daily use of 0.5 - 0.1 g of cholesterol per 1 kg of body weight.

As a rule, they were accompanied by an increase in cholesterol levels in the blood serum (3-5 times compared to the initial level), which was the basis for the assumption of a leading pathogenetic role in the development of atherosclerosis-hypercholesterolemia. This model is easily reproducible not only in rabbits, but also in chickens, pigeons, monkeys, and pigs.

In dogs and rats resistant to cholesterol, atherosclerosis is reproduced by the combined effect of cholesterol and methylthiouracil, which suppresses thyroid function. This combination of two factors (exogenous and endogenous) leads to prolonged and severe hypercholesterolemia (over 26 mmol/l - 100 mg%). Adding butter and bile salts to food also contributes to the development of atherosclerosis.

In chickens (roosters), experimental atherosclerosis of the aorta develops after long-term (4 - 5 months) exposure to diethylstilbestrol. In this case, atherosclerotic changes appear against the background of endogenous hypercholesterolemia, resulting from a violation of the hormonal regulation of metabolism.

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Topic: Experimental atherosclerosis

1. Introduction: Experimental atherosclerosis

2. Vascular lesions that develop due to nutritional disorders

3. Changes in the aorta with hypervitaminosis D

4. Necrosis and aneurysm of the aorta in rats

5. Necrotizing arteritis

6. Vascular changes due to insufficient protein in food

7. Dystrophic-sclerotic changes in blood vessels obtained with the help of certain chemical substances

8. Aortitis obtained by mechanical thermal and infectious damage to the vascular wall

Literature

INTRODUCTION: EXPERIMENTAL ATHEROSCLEROSIS

Experimental reproduction of vascular changes similar to human atherosclerosis is achieved by feeding animals with food rich in cholesterol or pure cholesterol dissolved in vegetable oil. In the development of an experimental model of atherosclerosis highest value had studies by Russian authors.

In 1908 A.I. Ignatovsky was the first to establish that when rabbits are fed animal food, changes develop in the aorta that are very reminiscent of human atherosclerosis. In the same year A.I. Ignatovsky together with L.T. Mooro created a classic model of atherosclerosis, showing that when rabbits are fed egg yolk for 1y2-61/2 months, atheromatosis of the aorta develops, which, starting in the intima, moves to the tunica media. These data were confirmed by L.M. Starokadomsky (1909) and N.V. Stukkeem (1910). N.V. Veselkin, S.S. Khalatov and N.P. Anichkov found that the main active part of yolks is cholesterol (A.I. Moiseev, 1925). After this, pure OH cholesterol began to be used along with yolks to obtain atherosclerosis. I. Anichkov and S.S Khalatov, 1913).

To obtain atherosclerotic changes in the aorta and large vessels, adult rabbits are fed daily for 3-4 months with cholesterol dissolved in sunflower oil. Cholesterol is dissolved in heated sunflower oil so that a 5--10% solution is obtained, which is introduced into the stomach heated to 35--40 °; Every day the animal receives 0.2-0.3 g of cholesterol per 1 kg of weight. If an exact dosage of cholesterol is not required, it is given mixed with vegetables. Within 1.5-2 weeks, the animals develop hypercholesterolemia, gradually reaching very high numbers (up to 2000 mg% with a norm of 150 mg%). In the aorta, according to N. N. Anichkov (1947), the following changes unfold. On inner surface vessel, 3-4 weeks after the start of the experiment, oval-shaped spots and stripes appear, somewhat elevated. Gradually (by 60-70 days) rather large plaques form, protruding into the lumen of the vessel. They appear primarily in the initial part of the aorta above the valves and in the arch at the mouths of large cervical arteries; these changes subsequently spread along the aorta in the caudal direction (Fig. 14). Number and size of plaques

increase, they merge with each other to form continuous diffuse thickenings of the aortic wall. The same plaques form on the valves of the left heart, in the coronary, carotid and pulmonary arteries. Deposition of lipoids is observed in the walls of the central arteries of the spleen and in the small arteries of the liver.

T.A. Sinitsyn (1953) to obtain atherosclerosis of the main branches coronary arteries heart fed the rabbits for a long time with egg yolks (0.2 - 0.4 g of cholesterol) dissolved in milk, and at the same time injected them with 0.3 g of thiouracil. Each rabbit received 170-200 yolks during the experiment. At microscopic examination at an early stage, a diffuse accumulation of lipoids is detected in the interstitial substance of the aortic wall, especially between the internal elastic lamina and the endothelium. In the future there will be large cells(polyblasts and macrophages), accumulating lipoid substances in the form of birefringent drops of cholesterolseters. At the same time, in places where lipoids are deposited, elastic fibers are formed in large quantities, split off from the internal elastic lamina and located between the cells containing lipoids. Soon, first collagen and then collagen fibers appear in these places (N.N. Anichkov, 1947).

In studies carried out under the leadership of N. N. Anichkov, the process of reverse development of the changes described above was also studied. If, after 3-4 months of feeding animals with cholesterol, its administration is stopped, then a gradual resorption of lipoids from plaques occurs, which in rabbits continues for over two years. At the sites of large lipid accumulations, fibrous plaques are formed, with lipid residues and cholesterol crystals in the center. Pollack (1947) and Fistbrook (1950) indicate that as the weight of animals increases, the severity of experimental atherosclerosis increases.

For a long time, rabbits remained the only animal species used to produce experimental atherosclerosis. This is explained by the fact that, for example, in dogs, when fed even large amounts of cholesterol, the level of cholesterol in the blood rises slightly and atherosclerosis does not develop. However, Steiner et al. (1949) showed that if you combine feeding dogs with cholesterol with a decrease in thyroid function, significant hypercholesterolemia occurs and atherosclerosis develops. The dogs were administered thiouracil with food daily for 4 months in increasing quantities: during the first two months, 0.8 g, during the third month, 1 g, and then 1.2 g. At the same time, the dogs received daily with food 10 g of cholesterol, which was previously dissolved in ether and mixed with food; food was given to the dogs after the ether had evaporated. Control experiments have shown that long-term administration of thiouracil or cholesterol alone to dogs does not cause either significant hypercholesterolemia (4-00 mg% when the norm is 200 mg%) or atherosclerosis. At the same time, when dogs are given thiouracil and cholesterol at the same time, severe hypercholesterolemia (up to 1200 mg%) and atherosclerosis develop.

The topography of atherosclerosis in dogs, to a much greater extent than in rabbits, resembles human atherosclerosis: the most pronounced changes are in the abdominal aorta, significant atherosclerosis is observed in the large branches of the coronary arteries of the heart with a significant narrowing of the lumen of the vessel (Fig. 15), many plaques are noticeable in the arteries of the brain . Huper (1946) administered dogs daily jugular vein 50 ml of hydroxylcellulose solution of varying viscosity (5-6 times higher than plasma viscosity) and observed the development of atheromatosis and degenerative changes in the tunica media in the aorta. When assessing the severity of experimental atherosclerosis, one should take into account the instructions of Lindsay et al. (1952, 1955), who found that significant arteriosclerosis often occurs in old dogs and cats. Lipid deposits are usually insignificant, and cholesterol is not detected in them.

Bragdon and Boyle (1952) produced atherosclerosis in rats by intravenous injections of lipoproteins obtained from the serum of rabbits fed cholesterol. These lipoproteins were isolated, purified and concentrated by centrifugation at 30 thousand rpm with increased concentration serum salts to 1063. Excess salt was then removed by dialysis. With repeated daily injections in rats, significant deposits of lipoids appear in the wall of the aorta and large vessels. Chaikov, Lindsay, Lorenz (1948), Lindsay, Nichols and Chaikov (1.955) obtained atherosclerosis in birds by periodically injecting them subcutaneously with 1-2 tablets of diethylstilbestrol (each tablet contained 12-25 mg of the drug); the experiment lasted for 10 months.

The developing atherosclerosis in topography and morphogenesis did not differ from cholesterol. According to these authors, atherosclerosis in birds can be obtained in the usual way - by feeding cholesterol.

Reproduction of atherosclerosis in monkeys often ended in failure (Kawamura, cited by Mann et al., 1953). However, Mann et al. (1953) managed to obtain severe atherosclerosis of the aorta, carotid and femoral arteries when feeding them for 18-30 months with food rich in cholesterol, but containing insufficient amounts of methionine or cystine. Daily addition of 1 g of methionine to food prevents the development of atherosclerosis. Earlier, Rinehart and Greenberg (1949) obtained atherosclerosis in monkeys when they were kept for 6 months on a diet with a high amount of cholesterol and insufficient pyridoxine.

The development of experimental atherosclerosis can be accelerated or, conversely, slowed down. A number of researchers have observed a more intense development of atherosclerosis when feeding animals with cholesterol in combination with experimental hypertension. So, N.N. Anichkov (1914) showed that when the lumen of the abdominal aorta narrows by V"--2/3, the development of atherosclerosis in rabbits receiving 0.4 g of cholesterol daily is significantly accelerated. According to N.I. Anichkova, more intense atherosclerotic changes can be obtained in animals by feeding them cholesterol and daily intravenous injections of a solution of 1: 1000 adrenaline in an amount of 0.1-0.15 ml for 22 days. Wilens (1943) gave rabbits 1 g of cholesterol daily (6 days a week) and placed them in an upright position for 5 hours (also 6 times a week), which led to an increase blood pressure by 30-40%. The experiment lasted from 4 to 12 weeks; In these animals, atherosclerosis was significantly more pronounced than in controls (who were fed only cholesterol or placed in an upright position).

V.S. Smolensky (1952) observed a more intensive development of atherosclerosis in rabbits with experimental hypertension (narrowing of the abdominal aorta; wrapping one kidney with a rubber capsule and removing the other).

Yester, Davis and Friedman (1955) observed an acceleration of the development of atherosclerosis in animals when they were fed cholesterol in combination with repeated injections of epinephrine. The rabbits were given intravenous epinephrine daily at a rate of 25 mg per 1 kg of weight. This dose was increased after 3-4 days to 50 mg per 1 kg of weight. The injections lasted 15-20 days. During the same period, the animals received 0.6-0.7 g of cholesterol. The experimental animals showed more significant lipoid deposits in the aorta, compared to control rabbits that received only cholesterol.

Shmidtman (1932) showed the importance of increased functional load on the heart for the development of atherosclerosis of the coronary arteries. Rats received 0.2 g of cholesterol dissolved in vegetable oil daily with food. At the same time, the animals were forced to run on a treadmill every day. The experiment lasted for 8 months. Control rats received cholesterol, but did not run in the drum. In experimental animals, the heart was approximately 2 times larger than in control animals (mainly due to hypertrophy of the left ventricular wall); In them, atherosclerosis of the coronary arteries was especially pronounced: in some places the lumen of the vessel was almost completely closed by atherosclerotic plaque. The degree of development of atherosclerosis in the aorta in experimental and control animals was approximately the same.

K.K. Maslova (1956) found that when feeding rabbits with cholesterol (0.2 mg daily for 115 days) in combination with intravenous administration of nicotine (0.2 ml, 1% solution daily), lipoid deposition in the aortic wall occurs to a much greater extent, than in cases where rabbits receive only cholesterol. K.K. Maslova explains this phenomenon by the fact that dystrophic changes in blood vessels caused by nicotine contribute to a more intense accumulation of lipoids in their walls. Kelly, Taylor and Huss (1952), Prior and Hartmap (1956) indicate that in areas of dystrophic changes in the aortic wall (mechanical damage, short-term freezing), atherosclerotic changes are especially pronounced. At the same time, the deposition of lipoids in these places delays and distorts the course of restoration processes in the vessel wall.

A number of studies have shown the delaying effect of certain substances on the development of experimental atherosclerosis. Thus, when feeding rabbits with cholesterol and simultaneously giving them thyroidin, the development of atherosclerosis occurs much more slowly. V.V. Tatarsky and V.D. Zipperling (1950) found that thyroidin also promotes a more rapid reverse development of atheromatous plaques. Rabbits were given 0.5 g of cholesterol (0.5% solution in sunflower oil) into the stomach daily through a tube. After 3.5 months of feeding with cholesterol, thyroidin was started to be used: daily administration of 0.2 g of thyroidin in the form of an aqueous emulsion into the stomach through a tube for 1.5-3 months. In these rabbits, in contrast to the control ones (which were not injected with thyroidin), there was a steeper drop in hypercholesterolemia and a more pronounced reverse development of atheromatous plaques (fewer amounts of lipoids in the aortic wall, deposited mainly in the form of large droplets). Choline also has a retarding effect on the development of atherosclerosis.

Steiner (1938) gave rabbits 1 g of cholesterol 3 times a week with food for 3-4 months. In addition, the animals were given 0.5 g of choline daily in the form of an aqueous emulsion. It turned out that choli significantly delays the development of atherosclerosis. It has also been shown that under the influence of choline, a more rapid reversal of atheromatous plaques occurs (administration of choline to rabbits for 60 days after a preliminary 110-day feeding of cholesterol). Taper's data were confirmed by Bauman and Rush (1938) and Morrisop and Rosi (1948). Horlick and Duff (1954) found that the development of atherosclerosis is significantly delayed under the influence of heparin. Rabbits received 1 g of cholesterol daily with food for 12 weeks. At the same time, the animals were given daily intramuscular injections 50 mg heparin. In treated rabbits, atherosclerosis was significantly less pronounced than in control rabbits that did not receive heparin. Similar results were previously obtained by Konstenides et al. (1953). Stumpf and Wilens (1954) and Gordon, Kobernik and Gardner (1954) found that cortisone delayed the development of atherosclerosis in rabbits fed cholesterol.

Duff and Mac Millap (1949) showed that in rabbits with alloxan diabetes the development of experimental atherosclerosis was significantly delayed. Rabbits were intravenously injected with a 5% aqueous solution of alloxyp (at the rate of 200 mg per 1 kg of weight). After 3-4 weeks (when diabetes developed), the animals were given cholesterol for 60-90 days (in total they received 45-65 g of cholesterol). In these animals, compared to control animals (without diabetes), atherosclerosis was significantly less pronounced. Some researchers have observed a sharp slowdown in the development of atherosclerosis in rabbits that, while receiving cholesterol, were exposed to general irradiation with ultraviolet rays. In these animals, the serum cholesterol content increased slightly.

Some vitamins have a significant effect on the development of atherosclerosis. It has been shown (A.L. Myasnikov, 1950; G.I. Leibman and E.M. Berkovsky, 1951) that the development of atherosclerosis is delayed under the influence of ascorbic acid. G.I. Leibman and E.M. Berkovsky gave rabbits 0.2 g of cholesterol per 1 kg of weight daily for 3 months. At the same time, the animals received daily ascorbic acid (0.1 g per 1 kg of weight). In these animals, atherosclerosis was less pronounced than in those that did not receive ascorbic acid. In rabbits receiving cholesterol (0.2 g daily for 3-4 months) in combination with vitamin D (10,000 units daily throughout the experiment), the development of atherosclerotic changes intensifies and accelerates (A.L Myasnikov, 1950).

According to Brager (1945), vitamin E promotes more intensive development of experimental cholesterol atherosclerosis: rabbits were given 1 g of cholesterol 3 times a week for 12 weeks; At the same time, intramuscular injections of 100 mg of vitamin E were given. All animals had higher hypercholesterolemia and more severe atherosclerosis compared to rabbits that did not receive vitamin E.

VASCULAR LESIONS DEVELOPING DURING NUTRITION DISORDERS. CHANGES IN THE AORTA WITH HYPERVITAMINOSIS D

Under the influence of large doses of vitamin D, animals develop pronounced changes in internal organs and large vessels. Kreitmayr and Hintzelman (1928) observed significant deposits of lime in the tunica media of the aorta in cats that were given 28 mg of irradiated ergosterol daily with food for a month (Fig. 16). Necrotic changes in the medial tunic of the aorta with subsequent calcification were discovered in rats by Dagaid (1930), who daily gave the animals 10 mg of irradiated ergosterol in a 1% solution in olive oil. Meessen (1952) gave rabbits 5000 sd for three weeks to obtain necrosis of the medial tunic of the aorta. vitamin Dg. Under these conditions, only microscopic changes occurred. Gilman and Gilbert (1956) discovered dystrophy of the middle tunica of the aorta in rats that were given 100,000 units for 5 days. vitamin D per 1 kg of weight. Vascular damage was more intense in animals that were given 40 mcg of thyroxine for 21 days before administration of vitamin D.

NECROSES AND ANEURYSMS OF THE AORTA IN RATS

When rats are fed for a long time with food containing large amounts of peas, dystrophic changes in the aortic wall develop with the gradual formation of an aneurysm. Bechhubur and Lalich (1952) fed white rats food containing 50% ground or coarse, unprocessed peas. In addition to peas, the diet included yeast, casein, olive oil, a salt mixture and vitamins. The animals were on a diet from 27 to 101 days. In 20 out of 28 experimental rats, an aortic aneurysm developed in the area of its arch. In some animals, the aneurysm ruptured with the formation of a massive hemothorax. Histological examination revealed edema of the medial membrane of the aorta, destruction of elastic fibers and minor hemorrhages. Subsequently, fibrosis of the wall developed with the formation of aneurysmal dilatation of the vessel. Panseti and Beard (1952) in similar experiments observed the development of an aneurysm in the thoracic aorta in 6 out of 8 experimental rats. Along with this, the animals developed kyphoscoliosis, which resulted from dystrophic changes in the vertebral bodies. Five animals died from aneurysm rupture and massive hemothorax at 5-9 weeks.

Walter and Wirtschaftsr (1956) kept young rats (from 21 days after birth) on a diet of 50% peas; in addition, the diet included: maize, casein, milk salt powder, vitamins. All this was mixed and given to the animals. The latter were killed 6 weeks after the start of the experiment. In contrast to the experiments cited above, in these experiments there was damage to the porta not only in the area of the arch, but also in other parts, including the abdominal. Histologically, vascular changes occurred in two, parallel developing processes: dystrophy and decay of the elastic frame, on the one hand, and fibrosis, on the other. Multiple intramural hematomas were usually observed. Significant changes have also taken place in pulmonary artery and coronary arteries of the heart. Some rats died due to aneurysm rupture; in a number of cases the latter had a delaminating character. Lulich (1956) showed that the described changes in the aorta are caused by P-amipopropiopitrite contained in peas.

NECROTIC ARTERITIS

Holman (1943, 1946) showed that dogs kept on a diet rich in fat, renal failure leads to the development of necrotizing arteritis. The animals were given food in which 32 parts were beef liver, 25 parts - cane sugar, 25 parts - starch grains, 12 parts - oil, 6 parts - fish oil; kaolin, salts and tomato juice. The experiment lasted 7-8 weeks (the time required for the occurrence of vascular lesions in the presence of renal failure). Kidney failure was achieved different ways: bilateral nephrectomy, subcutaneous injections of 0.5% aqueous solution of uranium nitrate at the rate of 5 mg per 1 kg of animal weight or intravenous injections of 1% aqueous solution of mercury chloride at the rate of 3 mg per 1 kg of animal weight. 87% of experimental animals developed necrotizing arteritis. Severe mural endocarditis was observed in the heart. Necrotizing arteritis developed only when feeding animals with food rich in fat was combined with renal failure. Each of these factors individually did not cause significant damage to the vessel walls.

VASCULAR CHANGES ARISING FROM INSUFFICIENT AMOUNT OF PROTEIN IN FOOD

Hanmap (1951) gave white mice food with the following composition (in percentage): sucrose - 86.5, casein - 4, salt mixture - 4, vegetable oil - 3, fish oil - 2, cystine - 0, 5; anhydrous mixture of glucose - 0.25 (0.25 g of this mixture contained 1 mg of riboflavin), para-aminobezoic acid - 0.1, inositol - 0.1. To 100 g of diet, 3 mg of calcium pantothenate, 1 mg of nicotinic acid, 0.5 mg of thiamine hydrochloride and 0.5 mg of pyridoxine hydrochloride were added. The mice died within 4-10 weeks. Damage to the aorta, pulmonary artery and blood vessels of the heart, liver, pancreas, lungs and spleen was observed. At an early stage, a basophilic, homogeneous substance appeared in the intima of the vessels, forming plaques slightly protruding under the endothelium: focal damage to the medial membrane occurred with the destruction of elastic fibers. The process ended with the development of arteriosclerosis with the deposition of lime in areas of degeneration.

DYSTROPHIC-SCLEROTIC CHANGES IN VESSELS OBTAINED USING SOME CHEMICALS

(adrenaline, nicotine, tyramine, diphtheria toxin, nitrates, high molecular weight proteins)

Josue (1903) showed that after 16-20 intravenous injections of adrenaline, significant degenerative changes develop in rabbits, mainly in the middle tunic of the aorta, ending in sclerosis and, in some cases, aneurysmal dilatation. This observation was subsequently confirmed by many researchers. Erb (1905) injected rabbits into an ear vein every 2-3 days with 0.1-0.3 mg of adrenaline in a 1% solution; injections continued for several weeks and even months. Rzhenkhovsky (1904) injected rabbits intravenously with 3 drops of a solution of adrenaline 1: 1000; injections were made daily, sometimes at intervals of 2-3 days for 1.5-3 months. To obtain adrenaline sclerosis, B.D. Ivanovsky (1937) injected rabbits intravenously daily or every other day with a solution of adrenaline I: 20,000 in an amount of 1 to 2 ml. Rabbits received up to 98 injections. As a result of long-term injections of adrenaline, sclerotic changes naturally develop in the aorta and large vessels. It is mainly the middle shell that is affected, where focal necrosis develops, followed by the development of fibrosis and calcification of necrotic areas.

Ziegler (1905) observed in a number of cases thickening of the intima, sometimes significant. Aneurysmal enlargements of the aorta may occur. Areas of sclerosis and calcification become visible macroscopically after 16-20 injections. Significant sclerotic changes also develop in the renal (Erb), iliac, carotid (Ziegler) arteries and in the viutororgan branches of large arterial trunks (B.D. Ivanovsky). B.D. Ivanovsky showed that under the influence of repeated injections of adrenaline, significant changes occur in small arteries and even capillaries. The wall of the latter thickens, becomes sclerotic, and the capillaries are no longer adjacent, as normally, directly to the parenchymal elements of the organs, but are separated from them by a thin connective tissue layer.

Walter (1950), studying changes in blood vessels during intravenous administration dogs with adrenaline in large doses (8 ml of solution 1: 1000 every 3 days), showed that already within 10 days and even earlier multiple hemorrhages are observed in the middle layer of the thoracic aorta, as well as in the small arteries of the heart, stomach, gall bladder, kidneys, colon. There is fibrinoid necrosis of the tunica media and severe paparteritis with a perivascular cellular reaction. Preliminary administration of diabsiamin to animals prevents the development of these changes.

Davis and Uster (1952) showed that with a combination of intravenous injections of ep i e f r i a (25 mg per 1 kg of weight) and thyroxine (subcutaneous administration daily of 0.15 mg per 1 kg of weight) to rabbits, sclerotic changes in the aorta are especially pronounced. With daily subcutaneous injections of 500 mg of ascorbic acid into animals, the development of arteriosclerosis is noticeably delayed. Preliminary removal of the thyroid gland inhibits the development of arteriosclerosis caused by epinephrine (adrenaline). Dystrophic changes in the medial tunic of the aorta and large vessels with calcification and formation of cysts were observed by Huper (1944) in dogs that had experienced histamine in the cheek. Histamine was administered subcutaneously in a mixture with beeswax and mineral oil at the rate of 15 mg per 1 kg of animal weight (see getting stomach ulcers with histamine).

Previously, Hooper and Lapsberg (1940) showed that in case of poisoning of dogs, er itol tetra nitrate O"m (administered orally for 32 weeks daily, in increasing doses from 0.00035 g to 0.064 g) or nitrogen acid With sodium (administration by mouth for several weeks, 0.4 g daily), pronounced dystrophic changes occur, mainly in the middle layer of the pulmonary artery and its branches. Significant lime deposits in some cases lead to a sharp narrowing Huper (1944) observed the development of necrosis of the medial tunic of the aorta, followed by calcification and the formation of cysts in dogs, which were injected into the vein with a solution of methylcellulose in increasing quantities (from 40 to 130 ml) 5 times a week.The experiment lasted for six months. .

Changes in the aorta similar to those described above can be obtained in animals with repeated injections of nicotin. A. 3. Kozdoba (1929) injected 1-2 ml of nicotine solution into the ear vein of rabbits daily for 76-250 days (average daily dose - 0.02-1.5 mg). Cardiac hypertrophy and dystrophic changes in the artery, accompanied by aneurysmal dilatation, were observed. All animals had significant enlargement of the adrenal glands. E. A. Zhebrovsky (1908) discovered necrosis of the middle tunic of the aorta with subsequent calcification and sclerosis in rabbits, which he placed daily for 6-8 hours under a cap filled with tobacco smoke. The experiments continued for 2-6 months. K. K. Maslova (1956) noted dystrophic changes in the aortic wall after daily intravenous injections of 0.2 ml of 1% nicotine solution into rabbits for 115 days. Bailey (1917) obtained pronounced dystrophic changes in the medial tunic of the aorta and large arteries with necrosis and multiple aneurysms with daily intravenous injections of 0.02-0.03 ml of diphtheric toxin into rabbits for 26 days.

Duff, Hamilton and Morgan (1939) observed the development of necrotizing arteritis in rabbits under the influence of repeated injections of tyramine (intravenous administration of 50-100 mg of the drug in the form of a 1% solution). The experiment lasted for 106 days. The majority of rabbits had pronounced changes in the aorta, large arteries and arterioles of the kidneys, heart and brain, and in each individual case the vessels of not all three organs, but one of them, were usually affected. In the aorta, necrosis of the middle membrane occurred, often quite significant; similar changes were found in the large vessels of the kidneys. In the heart, kidneys and brain, arteriolecrosis was observed with subsequent hyalnosis of the vascular step. Some rabbits developed massive hemorrhage in the brain due to arteriolecrosis.

AORTITS OBTAINED BY MECHANICAL THERMAL AND INFECTIOUS DAMAGE OF THE VASCULAR WALL

In order to study the patterns of inflammatory and reparative processes in the aortic wall, some researchers use mechanical damage to the vessel. Prpor and Hartman (1956), after opening the abdominal cavity, cut off the aorta and damage the steica by piercing it with a thick needle with a sharp, curved end. Baldwin, Taylor and Hess (1950) damaged the aortic wall by short-term exposure to low temperature. To do this, the aorta is exposed in the abdominal section and a narrow tube is applied to the wall, into which carbon dioxide is injected. The aortic wall is frozen for 10-60 seconds. At the end of the second week after freezing, due to necrosis of the tunica media, an aortic aneurysm develops. In half of the cases, calcification of the damaged areas occurs. Metaplaetic formation of bone and cartilage often occurs. The latter appears no earlier than the fourth week after injury, and the bone appears after 8 weeks. A. Soloviev (1929) cauterized the aortic wall and Carotid arteries hot thermal cautery. Schlichter (1946) To obtain aortic necrosis in dogs, he burned its wall with a burner. Pronounced changes in the inner lining (hemorrhages, necrosis) in some cases caused the rupture of the vessel. If this did not happen, sclerosis of the wall developed with calcification and the formation of small cavities. N. Andrievich (1901) injured the wall of the arteries by cauterizing it with a solution of silver nitrate; in some cases, after this, the affected segment was wrapped in celloidin, which, irritating the wall of the vessel, made the damage more significant.

Talquet (1902) obtained purulent inflammation of the vessel wall by introducing a staphylococcus culture into the surrounding tissue. Previously, Krok (1894) showed that purulent arteritis occurs when an animal is given an intravenous culture of microorganisms only if the vessel wall is first damaged. F.M. Khaletskaya (1937) studied the dynamics of the development of infectious aortitis, which develops as a result of the transition of the inflammatory process from the pleura to the aortic wall. Rabbits between the 6th and 7th ribs pleural cavity a fistula tube was inserted. The hole remained open for 3-5 days, and in some experiments for three months. After 3-5 days, fibrous-purulent pleurisy and pleural empyema developed. The transition of the process to the aortic wall was often observed. In the latter, necrosis of the middle shell initially occurred; they developed earlier than inflammatory process spread to the aorta, and, but in the opinion of F.M. Khaletskaya, were caused by vasomotor disorders due to intoxication (primary dystrophy and necrosis of the medial membrane). If suppuration spread to the aorta, the outer, middle and inner membranes were successively involved in the inflammatory process with the development of secondary necrotic changes.

Thus, the process ended with sclerosis of the vascular wall with the formation of small and large scars. Thromboarteritis was observed in the inner membrane, ending with thickening and sclerosis of the intima.

Literature:

Anichkov N.N. Beitr. pathol. Anat. u. allg. Pathol.. Bel 56, 1913.

Anichkov II.II. Verh. d. deutsch, pathol. Ges., 20:149, 1925.

Anichkov II.H. News, khpr. and Potrap, region, vol. 16--17 book 48--49 p. 105, 1929.

Anichkov II.P. Experimental studies on atherosclerosis. In the book: L. I. Abrikosov. Private pathologist, anatomy vol. 2 p. 378, 1947.

Valdez A.O. Arch. pathol., 5, 1951.

Walker F.I. Experimental data on phlebitis, thrombosis and embolism. Sat. works, pos.vyashch. 40th anniversary of the activity of V. N. Shevkunenko, L., 1937.

Vartapetov B.L. Doctor. case, 1. 4 3. 1941.

Vartapetov B.L. Doctor. case. 11 -- 12. 848, 1946.

Vinogradov S.A. Arch. pathologist, 2, 1950.

Vinogradov S.A. Arch. pathol., 1, 1955.

Vinogradov S.A. Bulletin exp. bpol. and med., 5, 1956.

Vishnevskaya O.II. All conf. pathologist Theses of the report, L. 1954.

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Topic: Experimental atherosclerosis

1. Introduction: Experimental atherosclerosis

2. Vascular lesions that develop due to nutritional disorders

3. Changes in the aorta with hypervitaminosis D

4. Necrosis and aneurysm of the aorta in rats

5. Necrotizing arteritis

6. Vascular changes due to insufficient protein in food

7. Dystrophic-sclerotic changes in blood vessels obtained with the help of certain chemicals

8. Aortitis obtained by mechanical thermal and infectious damage to the vascular wall

Literature

INTRODUCTION: EXPERIMENTAL ATHEROSCLEROSIS

To obtain atherosclerotic changes in the aorta and large vessels, adult rabbits are fed daily for 3-4 months with cholesterol dissolved in sunflower oil. Cholesterol is dissolved in heated sunflower oil so that a 5-10% solution is obtained, which is introduced into the stomach heated to 35-40 °; Every day the animal receives 0.2-0.3 g of cholesterol per 1 kg of weight. If an exact dosage of cholesterol is not required, it is given mixed with vegetables. Within 1.5-2 weeks, the animals develop hypercholesterolemia, gradually reaching very high numbers (up to 2000 mg% compared to the norm of 150 mg%). In the aorta, according to N. N. Anichkov (1947), the following changes unfold. On the inner surface of the vessel, 3-4 weeks after the start of the experiment, oval-shaped spots and stripes, somewhat elevated, appear. Gradually (by 60-70 days) rather large plaques form, protruding into the lumen of the vessel. They appear primarily in the initial part of the aorta above the valves and in the arch at the mouths of the large cervical arteries; these changes subsequently spread along the aorta in the caudal direction (Fig. 14). Number and size of plaques

T.A. Sinitsyna (1953) to obtain atherosclerosis of the main branches of the coronary arteries of the heart, fed rabbits for a long time with egg yolks (0.2 - 0.4 g of cholesterol) dissolved in milk, and at the same time injected them with 0.3 g of thiouracil. Each rabbit received 170-200 yolks during the experiment. Microscopic examination at an early stage reveals a diffuse accumulation of lipoids in the interstitial substance of the aortic wall, especially between the internal elastic lamina and the endothelium. Subsequently, large cells (polyblasts and macrophages) appear, accumulating lipid substances in the form of birefringent drops of cholesterol seters. At the same time, in places where lipoids are deposited, elastic fibers are formed in large quantities, split off from the internal elastic lamina and located between the cells containing lipoids. Soon, first collagen and then collagen fibers appear in these places (N.N. Anichkov, 1947).

For a long time, rabbits remained the only animal species used to produce experimental atherosclerosis. This is explained by the fact that, for example, in dogs, when fed even large amounts of cholesterol, the level of cholesterol in the blood rises slightly and atherosclerosis does not develop. However, Steiner et al. (1949) showed that if you combine feeding dogs with cholesterol with a decrease in thyroid function, significant hypercholesterolemia occurs and atherosclerosis develops. The dogs were given thiouracil with food daily for 4 months in increasing quantities: during the first two months, 0.8 g, during the third month, 1 g, and then 1.2 g. At the same time, the dogs received daily with food 10 g of cholesterol, which was previously dissolved in ether and mixed with food; food was given to the dogs after the ether had evaporated. Control experiments have shown that long-term administration of thiouracil or cholesterol alone to dogs does not cause either significant hypercholesterolemia (4-00 mg% when the norm is 200 mg%) or atherosclerosis. At the same time, when dogs are given thiouracil and cholesterol at the same time, severe hypercholesterolemia (up to 1200 mg%) and atherosclerosis develop.

The topography of atherosclerosis in dogs, to a much greater extent than in rabbits, resembles human atherosclerosis: the most pronounced changes are in the abdominal aorta, significant atherosclerosis is observed in the large branches of the coronary arteries of the heart with a significant narrowing of the lumen of the vessel (Fig. 15), many plaques are noticeable in the arteries of the brain . Huper (1946) injected dogs daily into the jugular vein with 50 ml of hydroxylcellulose solution of varying viscosity (5-6 times the viscosity of plasma) and observed the development of atheromatosis and degenerative changes in the tunica media in the aorta. When assessing the severity of experimental atherosclerosis, one should take into account the instructions of Lindsay et al. (1952, 1955), who found that significant arteriosclerosis often occurs in old dogs and cats. Lipid deposits are usually insignificant, and cholesterol is not detected in them.

Bragdon and Boyle (1952) produced atherosclerosis in rats by intravenous injections of lipoproteins obtained from the serum of rabbits fed cholesterol. These lipoproteins were isolated, purified and concentrated by centrifugation at 30 thousand rpm with the serum salt concentration increased to 1063. Excess salt was then removed by dialysis. With repeated daily injections in rats, significant deposits of lipoids appear in the wall of the aorta and large vessels. Chaikov, Lindsay, Lorenz (1948), Lindsay, Nichols and Chaikov (1.955) obtained atherosclerosis in birds by periodically injecting them subcutaneously with 1-2 tablets of diethylstilbestrol (each tablet contained 12-25 mg of the drug); the experiment lasted for 10 months.

Reproduction of atherosclerosis in monkeys often ended in failure (Kawamura, cited by Mann et al., 1953). However, Mann et al. (1953) managed to obtain pronounced atherosclerosis of the aorta, carotid and femoral arteries in apes when feeding them for 18-30 months with food rich in cholesterol, but containing insufficient amounts of methionine or cystine. Daily addition of 1 g of methionine to food prevents the development of atherosclerosis. Previously, Rinehart and Greenberg (1949) obtained atherosclerosis in monkeys when they were kept for 6 months on a diet with a high amount of cholesterol and insufficient pyridoxine.

The development of experimental atherosclerosis can be accelerated or, conversely, slowed down. A number of researchers have observed a more intense development of atherosclerosis when feeding animals with cholesterol in combination with experimental hypertension. So, N.N. Anichkov (1914) showed that when the lumen of the abdominal aorta is narrowed by V"-2/3, the development of atherosclerosis in rabbits receiving 0.4 g of cholesterol daily is significantly accelerated. According to N.I. Anichkova, more intense atherosclerotic changes can be obtained in animals by feeding them cholesterol and daily intravenous injections of a solution of 1: 1000 adrenaline in an amount of 0.1-0.15 ml for 22 days. Wilens (1943) gave rabbits 1 g of cholesterol daily (6 days a week) and placed them in an upright position for 5 hours (also 6 times a week), which resulted in a 30-40% increase in blood pressure. The experiment lasted from 4 to 12 weeks; In these animals, atherosclerosis was significantly more pronounced than in controls (who were fed only cholesterol or placed in an upright position).

Yester, Davis and Friedman (1955) observed an acceleration of the development of atherosclerosis in animals when they were fed cholesterol in combination with repeated injections of epinephrine. The rabbits were given intravenous epinephrine daily at a rate of 25 mg per 1 kg of weight. This dose was increased after 3-4 days to 50 mg per 1 kg of weight. The injections lasted 15 - 20 days. During the same period, the animals received 0.6-0.7 g of cholesterol. The experimental animals showed more significant lipoid deposits in the aorta, compared to control rabbits that received only cholesterol.

A number of studies have shown the delaying effect of certain substances on the development of experimental atherosclerosis. Thus, when feeding rabbits with cholesterol and simultaneously giving them thyroidin, the development of atherosclerosis occurs much more slowly. V.V. Tatarsky and V.D. Zipperling (1950) found that thyroidin also promotes a more rapid reverse development of atheromatous plaques. Rabbits were given 0.5 g of cholesterol (0.5% solution in sunflower oil) into the stomach daily through a tube. After 3.5 months of feeding with cholesterol, they began to use thyroidin: daily administration of 0.2 g of thyroidin in the form of an aqueous emulsion into the stomach through a tube for 1.5-3 months. In these rabbits, in contrast to the control ones (which were not injected with thyroidin), there was a steeper drop in hypercholesterolemia and a more pronounced reverse development of atheromatous plaques (fewer amounts of lipoids in the aortic wall, deposited mainly in the form of large droplets). Choline also has a retarding effect on the development of atherosclerosis.

Steiner (1938) gave rabbits 1 g of cholesterol 3 times a week with food for 3-4 months. In addition, the animals were given 0.5 g of choline daily in the form of aqueous

emulsions. It turned out that choli significantly delays the development of atherosclerosis. It has also been shown that under the influence of choline, a more rapid reversal of atheromatous plaques occurs (administration of choline to rabbits for 60 days after a preliminary 110-day feeding of cholesterol). Taper's data were confirmed by Bauman and Rush (1938) and Morrisop and Rosi (1948). Horlick and Duff (1954) found that the development of atherosclerosis is significantly delayed under the influence of heparin. Rabbits received 1 g of cholesterol daily with food for 12 weeks. At the same time, the animals received intramuscular injections of 50 mg of heparin daily. In treated rabbits, atherosclerosis was significantly less pronounced than in control rabbits that did not receive heparin. Similar results were previously obtained by Konstenides et al. (1953). Stumpf and Wilens (1954) and Gordon, Kobernik and Gardner (1954) found that cortisone delayed the development of atherosclerosis in rabbits fed cholesterol.

VASCULAR LESIONS DEVELOPING DURING NUTRITION DISORDERS. CHANGES IN THE AORTA WITH HYPERVITAMINOSIS D

NECROSES AND ANEURYSMS OF THE AORTA IN RATS

When rats are fed for a long time with food containing large amounts of peas, dystrophic changes in the aortic wall develop with the gradual formation of an aneurysm. Bechhubur and Lalich (1952) fed white rats food containing 50% ground or coarse, unprocessed peas. In addition to peas, the diet included yeast, casein, olive oil, a salt mixture and vitamins. The animals were on a diet from 27 to 101 days. In 20 out of 28 experimental rats, an aortic aneurysm developed in the area of its arch. In some animals, the aneurysm ruptured with the formation of a massive hemothorax. Histological examination revealed edema of the medial membrane of the aorta, destruction of elastic fibers and minor hemorrhages. Subsequently, fibrosis of the wall developed with the formation of aneurysmal dilatation of the vessel. Panseti and Beard (1952) in similar experiments observed the development of an aneurysm in the thoracic aorta in 6 out of 8 experimental rats. Along with this, the animals developed kyphoscoliosis, which resulted from dystrophic changes in the vertebral bodies. Five animals at 5-9 weeks died from aneurysm rupture and massive hemothorax.

Walter and Wirtschaftsr (1956) kept young rats (from 21 days after birth) on a diet of 50% peas; in addition, the diet included: maize, casein, milk salt powder, vitamins. All this was mixed and given to the animals. The latter were killed 6 weeks after the start of the experiment. In contrast to the experiments cited above, in these experiments there was damage to the porta not only in the area of the arch, but also in other parts, including the abdominal. Histologically, changes in blood vessels occurred in two parallel developing processes: degeneration and disintegration of the elastic framework, on the one hand, and fibrosis, on the other. Multiple intramural hematomas were usually observed. Significant changes also occurred in the pulmonary artery and coronary arteries of the heart. Some rats died due to aneurysm rupture; in a number of cases the latter had a delaminating character. Lulich (1956) showed that the described changes in the aorta are caused by P-amipopropiopitrite contained in peas.

NECROTIC ARTERITIS

Holman (1943, 1946) showed that in dogs kept on a diet rich in fat, renal failure leads to the development of necrotizing arteritis. The animals were given food in which 32 parts were beef liver, 25 parts - cane sugar, 25 parts - starch grains, 12 parts - oil, 6 parts - fish oil; Kaolin, salts and tomato juice were added to this mixture. The experiment lasted 7-8 weeks (the time required for vascular lesions to occur in the presence of renal failure). Renal failure was achieved in various ways: bilateral nephrectomy, subcutaneous injections of a 0.5% aqueous solution of uranium nitrate at a rate of 5 mg per 1 kg of animal weight, or intravenous injections of a 1% aqueous solution of mercury chloride at a rate of 3 mg per 1 kg of animal weight. 87% of experimental animals developed necrotizing arteritis. Severe mural endocarditis was observed in the heart. Necrotizing arteritis developed only when animals were fed a diet rich in fat in combination with renal failure. Each of these factors individually did not cause significant damage to the vessel walls.

VASCULAR CHANGES ARISING FROM INSUFFICIENT AMOUNT OF PROTEIN IN FOOD

Hanmap (1951) gave white mice food with the following composition (in percentage): sucrose - 86.5, casein - 4, salt mixture - 4, vegetable oil - 3, fish oil - 2, cystine - 0.5; anhydrous mixture of glucose - 0.25 (0.25 g of this mixture contained 1 mg of riboflavin), para-aminobezoic acid - 0.1, inositol - 0.1. To 100 g of diet, 3 mg of calcium pantothenate, 1 mg of nicotinic acid, 0.5 mg of thiamine hydrochloride and 0.5 mg of pyridoxine hydrochloride were added. The mice died within 4-10 weeks. Damage to the aorta, pulmonary artery and blood vessels of the heart, liver, pancreas, lungs and spleen was observed. At an early stage, a basophilic, homogeneous substance appeared in the intima of the vessels, forming plaques slightly protruding under the endothelium: focal damage to the medial membrane occurred with the destruction of elastic fibers. The process ended with the development of arteriosclerosis with the deposition of lime in areas of degeneration.

DYSTROPHIC-SCLEROTIC CHANGES IN VESSELS OBTAINED USING SOME CHEMICALS

(adrenaline, nicotine, tyramine, diphtheria toxin, nitrates, high molecular weight proteins)

Walter (1950), studying changes in blood vessels during the intravenous administration of adrenaline to dogs in large doses (8 ml of a solution of 1: 1000 every 3 days), showed that already within 10 days and even earlier, multiple hemorrhages were observed in the middle tunic of the thoracic aorta, and also in the small arteries of the heart, stomach, gall bladder, kidneys, and colon. There is fibrinoid necrosis of the tunica media and severe paparteritis with a perivascular cellular reaction. Preliminary administration of diabsiamin to animals prevents the development of these changes.

Davis and Uster (1952) showed that with a combination of intravenous injections of ep i e f r i a (25 mg per 1 kg of weight) and thyroxine (subcutaneous administration daily of 0.15 mg per 1 kg of weight) to rabbits, sclerotic changes in the aorta are especially pronounced. With daily subcutaneous injections of 500 mg of ascorbic acid into animals, the development of arteriosclerosis is noticeably delayed. Preliminary removal of the thyroid gland inhibits the development of arteriosclerosis caused by epinephrine (adrenaline). Dystrophic changes in the medial tunic of the aorta and large vessels with calcification and formation of cysts were observed by Huper (1944) in dogs that had experienced histamine in the cheek. Histamine was administered subcutaneously in a mixture with beeswax and mineral oil at the rate 15 mg per 1 kg of animal weight (see getting stomach ulcers with histamine).

Changes in the aorta similar to those described above can be obtained in animals with repeated injections of nicotin. A. 3. Kozdoba (1929) injected 1-2 ml of nicotine solution into the ear vein of rabbits daily for 76-250 days (average daily dose - 0.02-1.5 mg). Cardiac hypertrophy and dystrophic changes in the artery, accompanied by aneurysmal dilatation, were observed. All animals had significant enlargement of the adrenal glands. E. A. Zhebrovsky (1908) discovered necrosis of the medial tunic of the aorta with subsequent calcification and sclerosis in rabbits, which he placed daily for 6-8 hours under a hood filled with tobacco smoke. The experiments continued for 2-6 months. K. K. Maslova (1956) noted dystrophic changes in the aortic wall after daily intravenous injections of 0.2 ml of 1% nicotine solution into rabbits for 115 days. Bailey (1917) obtained pronounced dystrophic changes in the medial tunic of the aorta and large arteries with necrosis and multiple aneurysms with daily intravenous injections of 0.02-0.03 ml of diphtheric toxin into rabbits for 26 days.

AORTITS OBTAINED BY MECHANICAL THERMAL AND INFECTIOUS DAMAGE OF THE VASCULAR WALL

In order to study the patterns of inflammatory and reparative processes in the aortic wall, some researchers use mechanical damage to the vessel. Prpor and Hartman (1956), after opening the abdominal cavity, cut off the aorta and damage the steica by piercing it with a thick needle with a sharp, curved end. Baldwin, Taylor and Hess (1950) damaged the aortic wall by short-term exposure to low temperature. To do this, the aorta is exposed in the abdominal section and a narrow tube is applied to the wall, into which carbon dioxide is injected. The aortic wall is frozen for 10-60 seconds. At the end of the second week after freezing, due to necrosis of the tunica media, an aortic aneurysm develops. In half of the cases, calcification of the damaged areas occurs. Metaplaetic formation of bone and cartilage often occurs. The latter appears no earlier than the fourth week after injury, and the bone - after 8 weeks. A. Soloviev (1929) cauterized the wall of the aorta and carotid arteries with a hot thermal cautery. Schlichter (1946) To obtain aortic necrosis in dogs, he burned its wall with a burner. Pronounced changes in the inner lining (hemorrhages, necrosis) in some cases caused the rupture of the vessel. If this did not happen, sclerosis of the wall developed with calcification and the formation of small cavities. N. Andrievich (1901) injured the wall of the arteries by cauterizing it with a solution of silver nitrate; in some cases, after this, the affected segment was wrapped in celloidin, which, irritating the wall of the vessel, made the damage more significant.

Talquet (1902) obtained purulent inflammation of the vessel wall by introducing a staphylococcus culture into the surrounding tissue. Previously, Krok (1894) showed that purulent arteritis occurs when an animal is given an intravenous culture of microorganisms only if the vessel wall is first damaged. F.M. Khaletskaya (1937) studied the dynamics of the development of infectious aortitis, which develops as a result of the transition of the inflammatory process from the pleura to the aortic wall. A fistula tube was inserted into the pleural cavity of rabbits between the 6th and 7th ribs. The hole remained open for 3-5 days, and in some experiments for three months. After 3-5 days, fibropurulent pleurisy and pleural empyema developed. The transition of the process to the aortic wall was often observed. In the latter, necrosis of the middle shell initially occurred; they developed earlier than the inflammatory process spread to the aorta, and, in the opinion of F.M. Khaletskaya, were caused by vasomotor disorders due to intoxication (primary dystrophy and necrosis of the medial membrane). If suppuration spread to the aorta, the outer, middle and inner membranes were successively involved in the inflammatory process with the development of secondary necrotic changes.

Let us especially consider the problem of modeling atherosclerosis. The experimental model of the latter is revealing in many respects.

The rabbit, a herbivore, is injected into gastrointestinal tract over a long period great amount cholesterol, i.e., a food product that is actually alien to it. But throughout human history, foods containing cholesterol have been normal dietary ingredients. Great value cholesterol for the diverse functions of the body is also reflected in the ability of the latter to synthesize cholesterol regardless of diet; the place of synthesis is, in particular, the arterial system, i.e., the walls of the arteries.

Alien food product for rabbits- cholesterol - floods the blood and, as a foreign chemical body, which does not have adequate enzyme systems in the rabbit’s body that break down cholesterol, or organs capable of releasing cholesterol into the external environment, is deposited in abundance in the reticuloendothelial system and in the arterial system, passing its endothelial barrier. This is the general fate of large-molecular compounds (such as methylcellulose, pectin, polyvinyl alcohol), which are not broken down by the body’s means and are not released by it.

Consequently, from a general theoretical standpoint that determines the essence of any model, the phenomenon obtained in rabbits has only an external resemblance to human arteriosclerosis. This similarity is morphological, chemical, but not etiological (ecological) and not pathogenetic.

The rabbit model of atherosclerosis is primarily the result of inadequate nutrition. It cannot, therefore, be considered as a model of human atherosclerosis and as a model of metabolic disorders of cholesterol metabolism, if only because deposits of foreign substances cannot be documentation of metabolic disorders of the same substances, just as, for example, lead deposits in bones do not document lead disorders exchange.

And the last thing: in human atherosclerosis, the issue of cholesterol metabolism disorders is resolved rather negatively.

The foregoing does not exclude the great cognitive significance of the same model.

The latter teaches that vascular barriers- a very conditional concept and that large molecular compounds can freely pass through them even outside of special dysoria, i.e. such forms of permeability of the vascular walls that occur during edema and inflammation. The model also emphasizes the importance of the arterial system in capturing all circulating chemical compounds, generally alien to the body or that have become so in the process, for example, of denaturation of protein bodies (amyloidosis, hyalinosis).

A methodologically important aspect of the same model is that it reveals the danger of one-sided judgments, in in this case based on purely morphological documentation.

“The problem of causality in medicine”, I.V. Davydovsky

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