Search

Intranasal administration of lysine- and arginine-containing peptides Lys-Lys-Arg-Arg-Pro-Gly-Pro and Lys-Arg-Arg-Lys-Pro-Gly-Pro was performed daily at a single dose of 100 µg/kg for 7 days on laboratory rats with experimental metabolic syndrome and endothelial dysfunction. Metabolic syndrome was modeled by a high-calorie diet maintained throughout the experimental period, while endothelial dysfunction was simulated by daily intraperitoneal injection of L–NAME at a single dose of 10 mg/kg for 5 days. It was found that these peptides had anticlotting, hypoglycemic, and lipid-lowering effects and reduced body weight gain in experimental rats. They affected both primary (vascular-platelet) hemostasis, decreasing platelet aggregation, and all elements of plasma hemostasis by increasing anticoagulant, fibrin-depolymerizing, and enzymatic fibrinolytic activities as well as anti-fibrin-stabilizing properties of plasma and reducing the concentration of fibrinogen in it. At the same time, the studied peptides diminished the content of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, while increasing the concentration of high-density lipoprotein cholesterol. These effects were observed 20 h after the last administration of peptides and persisted, although to a lesser extent, 7 days (168 h) after treatment withdrawal. In this regard, the prolonged action can be considered for both glyproline peptides containing lysine and arginine aminoacid residues in their structure and their ability to protect the body from the development of metabolic diseases and endothelial dysfunction. The maximum effects were provided by the Lys-Arg-Arg-Lys-Pro-Gly-Pro peptide, which may be associated with its structural features.

We studied the effect of chronic intranasal and peroral administration of a new peptide preparation AСTH15-18PGP in a dose of 100 mg/kg body weight on the state of vascular-platelet and plasma hemostasis in animals. It was found that this synthetic regulatory peptide administered intranasally can produce antiplatelet, anticoagulant, and antifibrin-stabilizing effects on the blood plasma in healthy rats. In both administration routes, the peptide induced activation of the anticoagulation system of the hemostasis by increasing enzymatic and non-enzymatic fibrinolysis; after intranasal administration, the fibrinolytic effects were more pronounced.

The search and research of pharmacological agents that could combine lipid-lowering and antithrombotic effects on the human organism are one of the most urgent and important tasks of modern biological and medical research. The unique effects of the regulatory peptides of the oxoproline series (5-охо-Pro- His-Pro-NH2, 5-oxo-Pro-Trp-Pro, and 5-oxo-Pro-Arg-Pro or Pyr-His-Pro-NH2, Pyr-Trp-Pro, and Pyr- Arg-Pro) synthesized by the methods of classical peptide chemistry have been found in animals with experimental hypercholesterolemia. Repeated intranasal administration of these peptides to animals with developed hypercholesterolemia increased their anticoagulant, fibrinolytic and antiplatelet potential of the blood and simultaneously lowered increased concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In addition, they promoted normalization of blood glucose. A week after the last administration of these peptides, the hypocholesterolemic, normoglycemic and anticoagulant effects persisted. The relationship between the structure of the oxoproline-containing peptides and their functional properties is discussed. It is concluded that further studies of oxoproline-containing peptides are promising in the context of development of pharmacological agents, combining the antithrombotic activity with the improvement of lipid metabolism in the body.

Functional characterization of new short glyproline peptides, which are able to provide a regulatory effect on the functional state of the hemostasis system, as well as lipid and carbohydrate metabolism in the body, is an actual task of physiology and medicine. In the present study, we used a model of experimental metabolic syndrome developed in animals due to continuous feeding with high-calorie food. This leads to increased clotting, glucose concentration, low-density lipoprotein cholesterol, triglycerides, and the level of total cholesterol in the blood, which is accompanied by an increase in the body weight of rats. Arginine-containing peptides (Arg-Glu-Arg-Pro-Gly-Pro, Arg-Glu-Arg-Val-Gly-Pro, Arg-Glu-Arg-Gly-Pro) were intranasally administered every 24 h to rats seven times 6 weeks after the development of metabolic syndrome. These peptides provided a unique combined effect on the body, restoring parameters of lipid metabolism, the hemostasis system, and the concentration of blood glucose to normal values. The corrective effect of the studied peptides was detected 20 h after the last administration and was maintained for 168 h even under further feeding of rats with high-calorie diet. The studied glyproline peptides belong to therapeutic normoglycemic and lipid-lowering drugs. They block the accumulation of new fat deposits in the body, and also have anticoagulant and antithrombotic effects in disorders of lipid metabolism. The Arg-Glu-Arg-Pro-Gly-Pro peptide possessed the most pronounced and stable positive effect on the body.

A comparative study of the influence of regulatory proline peptides Pro-Gly-Pro, Pro-Arg-Pro, Pro-Gly-Pro-Leu, and Arg-Pro-Gly-Pro on the state of the hemostasis system was carried out in an experiment on male rats with metabolic syndrome. Under these conditions, repeated (7-fold) intranasal administration of the peptides in a daily dose of 50 μg/kg resulted in an increase in the anticoagulant potential of the blood, namely, in an increase in the anticoagulant, fibrinolytic, and antiplatelet activity 20 h and 7 days after the last peptide injection. The arginine-containing peptide Arg-Pro-Gly-Pro had the most pronounced and stable effect on haemostasis under these experimental conditions.

Anticoagulant effects of 12 short peptides of the glyproline series - Arg-Glu-Arg-Pro-Gly-Pro (RERPGP), Arg-Glu-Arg-Val-Gly-Pro (RERVGP), Arg-Glu-Arg-Gly-Pro (RERGP), Arg-Pro-Gly-Pro (RPGP), Pro-Leu-Pro (PLP), Pro-Leu-Pro-Ala (PLPA), Pro-Gly-Pro-Leu (PGPL), Phe-Pro-Leu-Pro-Ala (FPLPA), Pyr-Arg-Pro (PyrRP), Lys-Lys-Arg-Arg-Pro-Gly-Pro (KKRRPGP), Arg-Lys-Lys-Arg-Pro-Gly-Pro (RKKRPGP), and Lys-Arg-Lys-Pro-Gly-Pro (KRKPGP) in concentrations of 10-3 and 10-2 mg/ml in vitro was demonstrated by the thromboelastographic method. The effects of 6 peptides ((RERPGP, RPGP, PLP, PLPA, RKKRPGP, and KKRRPGP) were also observed in vivo after intranasal or oral administration. Changes in the studied thromboelastographic parameters towards hypocoagulation in comparison with the control group were noted. Arginine and leucine glyprolines produced the maximum anticoagulant effect.

We studied the effect of chronic intranasal and peroral administration of a new peptide preparation AСTH

Comparative analysis of the hypocholesterolemic and antithrombotic action of small regulatory glyproline peptides (Pro-Gly-Pro, Arg-Pro-Gly-Pro and Pro-Gly-Pro-Leu) was performed on an experimental hypercholesterolemia model of rats. Repeated intranasal introduction of glyproline peptides to fat-diet-fed animals led to more active functioning of the anticoagulation system (the anticoagulant and fibrinolytic properties of the plasma increased and platelet aggregation decreased) and to normalization of the total cholesterol level as a parameter of lipid metabolism. The largest anticoagulant and hypocholesterolemic effect was detected for the Pro-Gly-Pro-Leu peptide. Hypothetical mechanisms of antithrombotic and hypocholesterolemic effects of glyproline peptides are presented.

Experimental data on the effect of the natural immunopeptide tuftsin and its synthetic counterpart on hemostasis parameters in vitro and in vivo when administered intranasally to animals (white laboratory rats) are given. It has been shown that in vitro both preparations induced a fibrin-depolymerization effect on fibrin that is not stabilized by factor XIIIa. For each preparation, it was noted that, when administered to rats, simultaneous antiplatelet, anticoagulant, and fibrin-depolymerization effects were observed in the blood plasma, with Selank having a more pronounced effect.

Blood coagulation was enhanced and all factors (total, enzyme, and non-enzyme) of the fibrinolytic system were suppressed in rats in 60 min after forced swimming test. Argininecontaining tetrapeptide glyproline Arg-Pro-Gly-Pro administered prior to this test activated fibrinolysis and prevented hypercoagulation. Administration of this peptide in 5 min after swimming test also enhanced anticoagulant, fibrinolytic, and antithrombotic activity of the blood. Therefore, glyproline Arg-Pro-Gly-Pro exerted both preventive and curative effects on the hemostasis system and prevented enhancement of blood coagulation provoked by emotional stress modeled by forced swimming test.

The lipid-lowering, fibrinolytic, and anticoagulant effects of leucine-containing glyprolines, Pro-Gly-Pro-Leu and Leu-Pro-Gly-Pro, were studied in vitro in the blood of patients with disorders of lipid metabolism. The lipid-lowering impact of glyprolines and their ability to reduce the polymerization and to increase the depolymerization of fibrin in human blood were found. Possible mechanisms of lipolytic action of peptides by means of modulation of the lipid-dependent phospholipase A2 were proposed.

One of the most urgent and important tasks of modern biological and medical research is the search and research of pharmacological agents that combine lipid-lowering and antithrombotic effects in the organism. The unique effects of the regulatory peptides of the oxoproline series (5-oхo-Pro-His-Pro-NH2, 5-oxo-Pro-Trp-Pro and 5-oxo-Pro-Arg-Pro or 5-oхo-Pro-His-Pro-NH2, Pyr-Trp-Pro and Pyr-Arg-Pro) have been found in rats with hypercholesterolemia (metabolic syndrome). Multiple intranasal of these peptides to animals with developed hypercholesterolemia increased anticoagulant, fibrinolytic and antiplatelet potential of the blood and simultaneously lowered increased concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides. In addition, they contributed to the normalization of blood glucose levels. A week after the last admistration of these peptides, the hypocholesterolemic, normoglycemic and anticoagulant effects persisted. The relationship between the structure of peptides of the oxoproline series and their functional properties is discussed. A conclusion is made about the prospects of further studies of oxoproline peptides as drugs that combine antithrombotic effects with the improvement of fat metabolism in the body.Odnoĭ iz aktual'nykh i vazhneĭshikh zadach sovremennykh biologicheskikh i meditsinskikh issledovaniĭ iavliaetsia poisk i issledovanie farmakologicheskikh sredstv, sochetaiushchikh gipolipidemicheskiĭ i antitromboticheskiĭ éffekty v organizme. V nastoiashcheĭ rabote u sintezirovannykh metodami klassicheskoĭ peptidnoĭ khimii v rastvore reguliatornykh peptidov oksoprolinovogo riada (5-okho-Pro-His-Pro-NH2, 5-oxo-Pro-Trp-Pro i 5-oxo-Pro-Arg-Pro ili Pyr-His-Pro-NH2, Pyr-Trp-Pro i Pyr-Arg-Pro) ustanovleny unikal'nye éffekty v organizme pri razvitii giperkholesterinemicheskikh sostoianiĭ. Issledovannye reguliatornye peptidy pri mnogokratnom intranazal'nom postuplenii v organizm zhivotnykh s razvivsheĭsia giperkholesterinemieĭ povyshali protivosvertyvaiushchiĭ (antikoaguliantnyĭ, fibrinoliticheskiĭ i antitrombotsitarnyĭ) potentsial krovi s odnovremennym podavleniem povyshennoĭ kontsentratsii obshchego kholesterina, kholesterina lipoproteinov nizkoĭ plotnosti i triglitseridov. Dopolnitel'no k étomu oni sposobstvovali normalizatsii urovnia gliukozy krovi. Spustia nedeliu posle otmeny primeneniia peptidov vyiavlennye u nikh gipokholesterinemicheskie, normoglikemicheskie i protivosvertyvaiushchie éffekty sokhranialis'. Obsuzhdaetsia vopros o sviazi struktury peptidov oksoprolinovogo riada i ikh funktsional'nykh svoĭstv. Delaetsia vyvod o perspektivnosti dal'neĭshikh issledovaniĭ oksoprolinovykh peptidov kak preparatov, sochetaiushchikh antitromboticheskoe deĭstvie s uluchsheniem lipidnogo obmena v organizme.

In the present work, the formation of the proline-heparin complex has been established. The way to synthesize the complex in vitro has been developed. The complex synthesized with the molar ratio of proline to heparin of 3: 1 extended the time of formation of a fibrin clot, reduced platelet aggregation, and showed a lytic effect towards nonstabilized fibrin in vitro conditions. Ten minutes after intravenous administration of the proline-heparin complex, there was an increase in levels of fibrin-depolymerization, anticoagulant, antifibrin-stabilizing and antiplatelet activity in blood of animals, whereas its components, proline and heparin, did not have such effects.

The experimental data on the therapeutic and prophylactic antidiabetogenic effect of di-, tri-, and tetrapeptides of the glyproline family with the additional inclusion of arginine or leucine at different positions are presented. The results are obtained using two animal models: with insulin-dependent diabetes mellitus (type 1), and persistent hyperglycemia similar to development of non-insulin-dependent diabetes mellitus (type 2) in humans. It is shown that repeated intranasal administration of Pro-Gly, Pro-Gly-Pro, Pro-Gly-Pro-Arg, Pro-Gly-Arg, Arg-Pro-Gly, Arg-Pro-Gly-Pro, Gly-Pro-Arg, Pro-Arg-Gly, Pro-Gly-Pro-Leu, Leu-Pro-Gly-Pro peptides to rats with hyperglycemia of different etiology led to the combined normoglycemic and anticoagulant effects in the blood plasma. The concept of the regulatory role of short proline-containing peptides, involving the universality of their action in the organism and directed towards the regulation of both hemostasis and insular systems in a variety of their physiological and clinical manifestations, was formulated.

Anticoagulant, fibrinolytic, and antiplatelet effects of RPGP peptide were found in animals under stress conditions caused by single or repeated immobilization. The observed properties of the peptide extend the study of agents protecting the organism under conditions of hypercoagulation occurring under stress conditions and help to re-evaluate the role of glyprolines as contributors to the maintenance of adaptation capacities in various pathologies.

Experimental data on the involvement of the blood anticoagulant system components (heparin complex compounds, short regulatory peptides) in fibrin formation processes are presented. Inhibition of thrombin activity and interactions of short glyproline peptides and their heparin complexes with fibrin monomer molecules are demonstrated. Peptides and their heparin complexes prevent the formation of primary polymeric fibrin and exhibit fibrin-depolymerizing activity on the formed polymeric fibrin. The mechanisms underlying the effects of heparin complexes on degradation of fibrin not stabilized with factor XIIIa is discussed on the basis of the results of spectral analysis and coagulation tests.

The participation of short glyproline peptides in regulating the metabolic processes of the body has been established. Experimental hypercholesterolemia and the development of metabolic syndrome in rats was caused by including foods with excess animal fat and carbohydrates in the diet, which eventually led to increased levels of cholesterol, triglycerides, and the atherogenic lipoproteins; hypercoagulation; and increased blood sugar. It was noted that glyprolines with different structures possess a unique combined effect on fat and carbohydrate metabolism, normalizing the characteristics of the lipid profile and blood sugar and protecting the organisms of animals from increased blood clotting. The idea of peptide regulation of the hemostatic system and metabolism of fats and carbohydrates in the development of metabolic syndrome was formulated.

Heparin was bound to the arginine-containing peptide Arg-Pro-Gly-Pro with the molar ratio of heparin to the peptide 1 : 1. The complex compound showed antiplatelet, anticoagulative, and fibrin-depolymerization activities. In an in vivo study, in type 2 diabetes progression, a 5-fold intranasal administration of the compound restored both impaired insular and anticlotting functions in rats. Furthermore, blood fibrinolytic and anticoagulative activities increased.

Aanalysis of the literature and our own research on the physiological effects of complex compounds of heparin with low molecular ligands (amino acids, regulatory peptides) is presented. It is proved that anticoagulative effects in blood flow were conditioned by the interaction of heparin with glioproline, immunopeptides, and other low molecular substances with formation of complex compounds. The presence of structural regions of binding of heparin and other components is established. It is indicated that in the blood of animals heparin complexes with low molecular ligands possess protective anticoagulative and antithrombotic effects. We made an attempt to reveal the possible mechanism of anticoagulative-fibrinolytic and antithrombotic action of complex compounds of heparin in the organism.

We discovered that simple proline-containing peptides Gly-Pro, Pro-Gly, Pro-Gly-Pro, and semax had an antistress protective effect on the organism appearing as anticoagulation system activation. Repeated intranasal injection of each of these peptides to rats prior to acute immobilization stress prevented a hypercoagulation response to prolonged stress lasting 60 min. At the same time there was increase of anti-thrombotic, anticoagulant, and fibrin depolymerization activity and recovery of enzymatic fibrinolytic activity. Dipeptides were found to have the greatest antistress effect. Our results showed that semax had a protective effect against enhanced blood coagulability resulting from repeated immobilization stress.

It has been shown that proline-containing peptides Gly-Pro and Gly-Pro-Arg in vitro had anticoagulant and nonenzymatic fibrinolytic activity. It was established that after intranasal introduction of these peptides to a rat, anticoagulant and fibrinolytic activity of enzymatic and nonenzymatic nature increased in the rat blood. The peptide protective effect against hypercoagulation induced by immobilization stress was found after repeated intranasal introduction of each peptide into the animal.

The acid-base and complexing properties of Logiparin (a low-molecular-weight variety (LMH) of heparin (H4L) with magnesium and calcium ions were studied using mathematical modeling of chemical equilibria in aqueous solutions of Logiparin and its solutions with magnesium and calcium ions and pH titration. The heparin concentration was set equal to the concentration of its disaccharide units. The protonated heparin form HL3− and the most significant heparin complexes of Mg2+ and Ca2+ were identified; relevant formation constants were estimated. Comparative analysis of the results is carried out against available data on ion complexing with unfractionated (high-molecular-weight) heparin (HMH). The Logiparin complexes of calcium and magnesium ions are inferior to the HMH complexes in both their formation constants in solution and their effect on the decrease in the equilibrium concentration of free calcium ions, a participant of all blood coagulation processes. This distinction creates prerequisites for the lower blood-coagulating activity of Logiparin compared to that of HMH, which is for the first time confirmed in biological experiments with the in vitro administration of the same concentration of HMH or LMH into the blood plasma of laboratory rats.

A significant and considerable decrease in abnormally high platelet aggregation has been demonstrated after intramuscular administration of sodium adenosine triphosphate (ATP) to rats with depressed anticoagulant system (in aging rats at the age of 11–12 months) and to rats with experimental diabetes both preliminarily and at the background of progressing diabetes. The elimination of one of thrombotic risk factors (decreasing elevated platelet aggregation) points to possible antithrombotic activity of ATP under these experimental conditions.

Biochemical methods confirmed the presence of the heparin-ATP complex. Acidic sulfur and carboxyl groups proved to mediate heparin-ATP complex formation. The technique for preparation of the heparin complex at a 1:20 weight ratio of the components and different pH was developed. Intramuscular administration of the resulting complex increased anticoagulant and fibrinolytic activities of animal (rat) plasma. The obtained data indicate the presence of physiologically active heparin-ATP complex providing for anticoagulant effects in the body.

A new method for the computer simulation of chemical equilibria in multicomponent biological liquids has been developed on the basis of a consistent analysis of the databank on equilibria in solutions, combined with the AUTOEQUIL program for the calculation of such equilibria. This method has been applied to the search for new low-molecular-weight endogenous blood anticoagulants with a mechanism of action based on reduction of the equilibrium concentration of biologically active Ca2+ ions by means of complex formation. Using the results of simulation of the metal-ion equilibria in blood plasma with a databank including over 800 units, an adequate model is created, which is capable of describing 64 equilibria in a basis set of 29 components. An analysis of these equilibria revealed four endogenous ligands capable of forming stable complexes with Ca2+, including glutamate (GLU), lactate (LAC), citrate (CIT) and adenosinetriphosphate (ATP). Their anticoagulant properties have been confirmed by universal biological assays in rats in terms of the plasma recalcification time (RCT) and the activated partial thromboplastin time (APTT). It has been found that the anticoagulant activities of components are as follows: LAC, 500%; ATP, 240%; GLU, 176%; CIT, 154%(relative to the substrate plasma activity of 100%).

We studied the effect of chronic intraperitoneal administration of heparin–lysine complex on the state of the hemostatic and insular systems in young and senescent animals (rats). This complex exerted a positive effect on physiological function of the coagulant, anticoagulant, and fibrinolytic components of the hemostatic system in the norm and in developing experimental alloxan diabetes. In this case, both the complex and its components, lysine and heparin, had a pronounced antidiabetogenic effect.

Natural heparin complexes proved to activate the anticoagulation system. The obtained experimental data convincingly confirm that glutamic acid alone, and particularly in a complex with heparin, has a considerable preventive potential and efficiently protects experimental animals with induced diabetes mellitus.

We studied the effect of influenza virus proteins—hemagglutinin, neuraminidase, nucleoprotein, and membrane protein—on hemostasis in vitro and in vivo. The results demonstrated that envelope proteins hemagglutinin and neuraminidase enhanced the fibrinolytic and anticoagulant activities of blood plasma and the activity of human tissue plasminogen activator. The membrane protein proved to have the highest activity among the core proteins of influenza virus; in contrast to hemagglutinin and neuraminidase, it inhibited fibrinolysis, increased the coagulant activity of blood plasma, and decreased the activity of human tissue plasminogen activator. The combined action of hemagglutinin and neuraminidase increased the plasma fibrinolytic and anticoagulant activities to a greater extent than the individual action of each agent. The combined action of hemagglutinin and membrane protein also increased the plasma fibrinolytic and anticoagulant activities, although to a lesser extent than the action of hemagglutinin alone. These data indicate that viral proteins are physiologically active and can cause influenza-specific disturbances of hemostasis.

Na/K-ATPase prepared from cerebellum granule cells of 10-12-day-old mice is inhibited by glutamate and its agonists, NMDA (ligand for ionotropic receptors) and ACPD (ligand for metabotropic receptors). The inhibition is specific and prevented by subsequent antagonists (MK-801 for ionotropic NMDA-receptors and MCPG for metabotropic receptors). The inhibiting effect of NMDA is significantly reversed by cysteine and that of ACPD by chelerythrine or indolyl maleimide. It is concluded that ionotropic receptors inhibit Na/K-ATPase because of intracellular production of reactive oxygen species, and metabotropic receptors mediate their effect via protein kinase C.

The experimental data on the therapeutic and prophylactic antidiabetogenic effect of di-, tri-, and tetrapeptides of the glyproline family with the additional inclusion of arginine or leucine at different positions are presented. The results are obtained using two animal models: with insulin-dependent diabetes mellitus (type 1), and persistent hyperglycemia similar to development of non-insulin-dependent diabetes mellitus (type 2) in humans. It is shown that repeated intranasal administration of Pro-Gly, Pro-Gly-Pro, Pro-Gly-Pro-Arg, Pro-Gly-Arg, Arg-Pro-Gly, Arg-Pro-Gly-Pro, Gly-Pro-Arg, Pro-Arg-Gly, Pro-Gly-Pro-Leu, Leu-Pro-Gly-Pro peptides to rats with hyperglycemia of different etiology led to the combined normoglycemic and anticoagulant effects in the blood plasma. The concept of the regulatory role of short proline-containing peptides, involving the universality of their action in the organism and directed towards the regulation of both hemostasis and insular systems in a variety of their physiological and clinical manifestations, was formulated.

The effects of semax on anticoagulant, fi brinolytic, and platelet components of the anticoagulation system were studied on albino rats under conditions of acute and chronic immobilization stress. Semax exhibited a protective antistress effect after repeated intranasal administration under conditions of hypercoagulation developing in response to immobilization stress of different degree. The effect manifested in stimulation of the anticoagulation system.

Fourfold intranasal administration of ATP was followed by an increase in anticoagulant activity and decrease in platelet aggregation in blood plasma of healthy rats and, particularly, of animals with suppressed function of the anticoagulant system. These changes decrease the risk of the prethrombotic state. Complex of ATP and high-molecular-weight heparin decreased platelet aggregation only in the blood from healthy animals, but increased anticoagulant potential of plasma hemostasis in prethrombotic animals.

Anticoagulant and nonenzymatic fibrinolytic activities increased in blood plasma of 6–7-month-old rats after repeated intramuscular administration of the heparin-adenosine triphosphate complex (G-ATP). The mixture of heparin and ATP had no fibrin depolymerizing activity in vitro. Repeated intramuscular administration of the mixture had anticoagulant effect although it was 1.5–1.6 times less pronounced compared to the complex. A higher anticoagulant and fibrinolytic efficiency of the G-ATP complex compared to the mixture is concluded.

ATP added to plasma samples in concentrations of 5x10(-3)-5x10(-5) M in vitro decreased ADP-induced platelet aggregation. Platelet aggregation stimulated with thrombin under similar experimental in vitro conditions significantly decreased in the presence of 5x10(-6) M ATP and tended to decrease under the influence of ATP in concentrations of 5x10(-3) and 5x10(-7)-5x10(-9) M ATP. When endogenous thrombin in the circulation was stimulated by intravenous infusion of tissue thromboplastin, pretreatment with ATP (4 intramuscular injections, 0.75 mg/kg) produced a correction effect and normalized disturbed anticoagulant activity and platelet aggregation.

The complex of high-molecular-weight heparin and ATP prevented thrombus formation in the blood flow. Repeated intramuscular injection of the complex increased total fibrinolytic activity of the blood, nonenzymatic fibrinolysis, and plasma anticoagulant activity and significantly decreased platelet aggregation.

Repeated intramuscular administration of the heparin-adenosine triphosphate (ATP) complex or ATP increased plasma anticoagulant and fibrinolytic activities and depressed the anticoagulation system in rats at the age of 10–11 months. Diabetogenic dose of alloxan induced no diabetes mellitus in such animals.

In rats with experimental hypercholesterolemia, 7-fold intranasal administration of the peptide Pro-Gly-Pro-Leu in a dose of 200 μg/kg body weight prevented the increase in blood glucose level and produced an anticoagulant effect.

It was found that 3-fold intranasal administration of Arg-Pro-Gly-Pro peptide in a dose of 1 mg/kg body weight under conditions of experimental persistent hyperglycemia prevents the development of diabetes in experimental rats and produces normoglycemic, anticoagulant, fibrinolytic, and antiplatelet effects.