RU2363454C1 - Method of preventing chronic toxic arterial hypertension and cardiopathy in experimental animals - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to experimental biology. A 30 mg/kg dose of acizole is administered hypodermically to an animal once everyday, together with a 40 mg/kg daily dose of lead acetate through a probe into the stomach.

EFFECT: design of a method, which allows for effective prevention of chronic toxic arterial hypertension and cardiopathy in experimental animals when investigating chronic toxic effect of heavy metals, particularly lead, on functional state of the cardiovascular system.

2 tbl, 1 ex, 2 dwg

Description

The invention relates to ecology, medicine, toxicology, experimental biology and can be used to study methods for the prevention of lesions in the chronic toxic effect of heavy metals, in particular lead, on the functional state of the cardiovascular system.

Anthropogenic pollution of the human environment is largely associated with trace elements from the heavy metal group, including lead, which is included in the list of priority pollutants by a number of international organizations, including WHO. Lead compounds are characterized by high toxicity, the ability to accumulate in the body, exerting a polytropic toxic effect (I. Trakhtenberg et al. 1994). Penetrating into the body, lead and its compounds contribute to the development of cardiovascular pathology, are a risk factor in the formation of myocardial dystrophy, arterial hypertension and coronary heart disease (Kirsankina E.V. 2003). The studies found a statistically significant increase in the relative risk of death from cardiovascular disease in workers exposed to lead aerosols in production compared with the control (O. Bardina et al., 1994; N.F. 1998, Izmerov). It is known that high doses of lead with prolonged exposure to the body increase the prevalence of high blood pressure (Solomenchuk T.M. 1996). Even relatively low concentrations of lead contribute to high blood pressure (Harlan W. 1988), which indicates the high toxicity of heavy metal.

In connection with the progressive deterioration of the environmental situation and a constant increase in the concentration of lead in the environment, the search for effective means of preventing its toxic effects on the human body is one of the most urgent problems of medicine.

There are many known drugs that restore metabolic processes, the violation of which occurs as a result of the toxic effects of heavy metals on the body. These include thiol compounds - unitiol, sodium thiosulfate, succimer, various complexones - disodium salt of ethylenediaminetetraacetic acid, pentacin, deferoxamine, etc. (Mashkovsky M.D. Medicines: in 2 volumes. T.2. - Kharkov “Torsing ", 1998. S.212-220). But along with the preventive and therapeutic effect, they can cause various side effects: disorders of the gastrointestinal tract, allergic reactions, leukopenia, etc. They can also remove trace elements, vital ions like iron, calcium, etc. from the body and cause metabolic disturbances. , which complicates their long-term use.

Acyzole was chosen as a means of restoring and stabilizing metabolic processes in the body during chronic lead poisoning. Acizole is a complex organozinc compound. Its chemical structure is bis (1-vinylimidazole) zinc diacetate. Atsizol was developed as an antihypoxic agent for carbon monoxide poisoning and is the only drug for the prevention and saving of life with this lesion. Acizole is a unique drug in its pharmacological properties and breadth of use, it does not have a toxic effect on the human and animal body, has no side effects. Acizole replenishes the concentration of zinc in enzymatic systems, helps to optimize the processes of tissue respiration, improves the oxygen-binding properties of blood, and thanks to its antihypoxic and antioxidant effect, acizole has a membrane-protective property.

Previously, acizole was used as an antidote for carbon monoxide poisoning, a hepatoprotector, an agent for the treatment of psoriasis, an adaptogen, a coronary anti-ischemic and antiarrhythmic agent.

The invention is aimed at solving the problem of developing a method for the prevention of chronic toxic arterial hypertension and cardiopathy in experimental animals.

The solution to this problem provides a significant reduction in arterial hypertension and cardiopathy in experimental animals with chronic lead poisoning by the membrane-protective effect of acyzole and its ability to optimize tissue respiration by improving the oxygen-binding properties of blood. The cytotoxicity of lead is due to two main pathophysiological mechanisms: increased lipid peroxidation due to a decrease in the antioxidant protection of the cell and inhibition of tissue respiration due to changes in the membrane potential of mitochondria and impaired activity of the respiratory chain enzymes. Atsizol, in turn, helps to optimize tissue respiration, improving the oxygen-binding properties of blood, helping to reduce disorders of tissue respiration; possessing antihypoxant and antioxidant effects, acyzole has a membrane protective effect, helping to stabilize the pathological process.

To achieve this technical result, the claimed invention is a method for the prevention of chronic toxic arterial hypertension and cardiopathy in experimental animals, characterized in that the animals are injected subcutaneously with acizole at a dose of 30 mg / kg daily once a day, along with the daily administration of lead acetate through a tube into the stomach at a dose of 40 mg / kg.

The proposed method is distinguished by the fact that for the first time a pharmacological preparation, acyzole, is used to prevent chronic toxic arterial hypertension and cardiopathy in experimental animals.

Between the signs of the proposed method and the result there is the following causal relationship: acyzole, contributing to the normalization of metabolic processes, stabilizing the processes of tissue respiration, having a membrane protective effect, reducing the toxic effect of lead on the body, has a detoxifying effect.

Prophylactic administration of acizole, subcutaneously at a dose of 30 mg / kg, every day, simultaneously with intragastric administration of a solution of lead acetate at a dosage of 40 mg / kg for 14 days, leads to a decrease in the severity of arterial hypertension and cardiopathy, to a significant restoration of the functions of the cardiovascular system . The inventive method is effective, cost-effective and easily reproducible.

According to the information available to the authors, the set of essential features characterizing the essence of the claimed invention is not known, which allows us to conclude that the invention meets the criterion of "novelty."

According to the authors, the essence of the claimed invention should not be obvious to specialists from a known level of medicine, since it does not reveal the above possibility of obtaining a method for the prevention of chronic toxic arterial hypertension and cardiopathy in experimental animals, including subcutaneous administration of acyzole every day, simultaneously with daily administration a solution of lead acetate through an atraumatic tube into the stomach for 14 days, which allows us to conclude that the criterion of "inventive cue level. "

The set of essential features characterizing the essence of the invention, in principle, can be repeatedly used in medicine to obtain a result consisting in an effective and easily reproducible method for the prevention of chronic toxic arterial hypertension and cardiopathy in experimental animals by pronounced membrane-protective action of the drug, which allows us to conclude that inventions the criterion of "industrial applicability".

This method is as follows.

To obtain a toxic substance, lead acetate is dissolved in sterile distilled water in such a way that 8 mg of lead (in terms of metal) falls per unit solution of 0.2 ml. For every 100 g of rat weight, 0.1 ml of a toxic solution is injected, which is not an excessive water load on the body of the experimental animal. Acyzole solution is prepared in such a way that for each unit of solution equal to 1 ml, 30 mg of acyzole is necessary. Acyzole solution for each injection is prepared daily before administration. A solution of lead acetate is injected through an atraumatic tube into the stomach at a dosage of 40 mg / kg, daily 1 time per day for 14 days to two groups of animals (No. 1 and No. 2). At the same time, from the first day of the administration of lead acetate, group No. 2 is administered subcutaneously with acizole at a dose of 30 mg / kg every day using a single-use insulin syringe. At the end of the experiment, the rats were killed using thiopental. For histological studies, tissue samples (heart) were fixed in 10% neutral formalin, and then subjected to paraffin embedding followed by preparation of sections 7-8 microns thick. Sections were stained with hematoxylin and eosin. The sections were studied in transmitted light using a Mikmed-1 microscope under an magnification of 80 * 200 * 400.

The essence of the method is confirmed morphologically. Figure 1 illustrates the morphological signs of cardiopathy. Histological examination of the heart in experimental animals in group No. 1 revealed (Figure 1), dystrophic changes in muscle fibers (a), their uneven staining with eosin (b), fragmentation and breakdown of fibers (c). The stroma is edematous, the vessels are full-blooded, their wall with signs of plasma impregnation and perivascular edema. Figure 2 illustrates the absence of morphological signs of cardiopathy. When histological examination of the heart in group No. 2 marked (Figure 2) mild dystrophic changes in muscle fibers, the fragmentation of which is not found. Histological examination data indicate the absence of signs of cardiopathy in animals of the second group, which indicates that acizole has the ability to weaken or prevent the toxic effect of lead on the myocardium in experimental animals with chronic lead poisoning.

Example. Two groups of male Wistar rats weighing 200-300 g were injected with a solution of lead acetate at a dose of 40 mg / kg every day for 14 days through an atraumatic tube into the stomach. At the same time, from the first day of the administration of lead acetate, group 2 every day received acizole at a dose of 30 mg / kg subcutaneously. At the end of the experiment (14 days) under the conditions of intraperitoneal anesthesia with sodium thiopental, the mean arterial pressure (SBP) was measured invasively (blood method) in all groups of animals through a plastic catheter filled with a 10% solution of heparin injected into the right femoral artery with an electroanometer. Registration was carried out on the MX-04 monitor with printout of data on an Epson LX-1050 + printer. According to a special formula, specific peripheral vascular resistance (OPSS) was calculated.

The results of the study showed that in rats with intragastric administration of lead acetate (group No. 1), there was a significant increase (p <0.001) in mean arterial pressure (SBP) compared with the intact group (Table 1). Arterial hypertension in the experimental group of animals is associated with a significant increase (p <0.001) in specific peripheral vascular resistance (Table 2). Against the background of simultaneous administration of acyzole in group No. 2, there was a significant decrease (p <0.001) in mean arterial pressure (Table 1), compared with group No. 1 with isolated administration of lead acetate, due to a significant decrease (p <0.001) in specific peripheral vascular resistance (table 2).

Table 1.
The effect of acizole on mean arterial pressure, against the background of intragastric administration of lead acetate at a dose of 40 mg / kg (M ± m). Experience Conditions Stat. indicator Mean arterial pressure (mmHg) Background M ± m 101.7 ± 1.43 14 days lead acetate (40 mg / kg) M ± m 120.2 ± 2.06 p *) 14 days lead acetate (40 mg / kg) + acizole (30 mg / kg) M ± m 105.10 ± 1.38 p **) Note: (*) - significant (p <0.001) change compared to the background. (**) - significant (p <0.001) change compared with the experimental group.

Table 2.
The effect of acizole on specific peripheral vascular resistance indices against the background of intragastric administration of lead acetate at a dose of 40 mg / kg (M ± m). Experience Conditions Stat. indicator Specific peripheral vascular resistance (conventional units) Background M ± m 1,547 ± 0,0294 14 days lead acetate (40 mg / kg) M ± m 1.923 ± 0.028 p *) 14 days lead acetate (40 mg / kg) + acizole (30 mg / kg) M ± m 1,694 ± 0,039 p **) Note: (*) - significant (p <0.001) change compared to the background. (**) - significant (p <0.001) change compared with the experimental group.

From the above it follows that the use of acizole is an effective way to prevent chronic toxic arterial hypertension and cardiopathy in experimental animals.

Claims (1)

A method for the prevention of chronic toxic arterial hypertension and cardiopathy in experimental animals, characterized in that the animals are injected subcutaneously with acyzole at a dose of 30 mg / kg daily once a day, along with a daily administration of lead acetate through a tube into the stomach at a dose of 40 mg / kg.

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