Antithrombotic Protective Effects of Arg-Pro-Gly-Pro Peptide during Emotional Stress Provoked by Forced Swimming Test in Rats.

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.

[Peptide Regulation of Metabolic Processes under Hypercholesterinemia Conditions of an Organism].

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.

Hypoglycemic and anticoagulant effects of tetrapeptide Pro-Gly-Pro-Leu in hypercholesterolemia.

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.

[Correction of impairments in functions of anticoagulation and insular systems of an organism by the regulatory peptide Leu-Pro-Gly-Pro].

It has been established that fivefold intranasal administration of the peptide Leu-Pro-Gly-Pro (1 mg/kg) to rats with developing refractory hyperglycemia leads to restoration and normalization of the functions of anticoagulation and insular systems. In the blood of experimental animals, there was a decrease in the sugar level and platelet aggregation and an increase in anticoagulant and all kinds of fibrinolytic (total, enzymatic, non-enzymatic, Hageman-dependent) activity.

[The modern concept of the regulatory role of peptides of the glyproline family in the correction of hemostasis system function during development of diabetes mellitus].

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.

[Cholesterol-lowering effect of the regulatory peptide Pro-Gly-Pro-Leu].

In the present paper anticoagulant-fibrinolytic effects of the peptide Pro-Gly-Pro-Leu in rats (370-500 g body weight) who consumed fatty foods with excess of saturated fatty acids (wheat flour and bread--35%, sugar--10%, margarine hydrogenated fats, mayonnaise, cheese--35% and offals--10%, cholesterol--1%, dry food--9%) has been established. The duration of the animals on the diet was 15 days. The experimental animals intranasally obtained peptide (200 microg/kg body weight per volume of 0.02 ml per 200 g body weight) 11 times (daily except weekends). Animals from the control group intranasally received instead of peptide its vehicle (0.85% solution of NaCl) at the same time and in the same amount. It has been shown that daily nasal administration of the regulatory tetrapeptide under fatty food intake for the entire period of the experiment has a positive effect on lipid metabolism. It warned the development of alimentary hypercholesterolemia, an increase in body weight, normalized disturbed lipid profile, blood cholesterol level. In addition, its administration also restored functional status of anticoagulation system and decreased elevated degree of blood coagulation to normal values. Possible mechanism of hypocholesterolemic activity of peptide can be explained by its ability to interact with receptors of blood or brain cells, and through a series of reactions mediated to reduce blood cholesterol levels. Thanks to the anti-platelet activity glyprolines effectively improves endothelial function and reduces the risk of blood clots in the blood vessels, providing improved rheological properties of blood and preventing the formation of atherosclerotic plaques in the arterial wall.

[A complex of heparin with the peptide Arg-Pro-Gly-Pro and its anticoagulative, fibrinolytic, and hyperglycemia effects].

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.

[Protective antithrombotic effects of proline-containing peptides in the animal body subjected to stress].

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 antithrombotic, 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.

[Comparative studies of anticoagulant and fibrinolytic effects of glyprolines Gly-Pro and Gly-Pro-Arg in conditions of 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.

[Effect of thyrotropin-releasing hormone and its synthetic analogue digipramine on certain hemostatic indices in vitro and in vivo].

The effect of neuropeptide thyrotropin-releasing hormone (TRH) and its synthetic analogue digipramine on certain indices of the blood coagulation system and fibrinolysis were studied in vitro and in vivo. The peptides added to the pool of normal rat plasma at 10(-10) to 10(-3) M increased the procoagulant activity but had virtually no effect on fibrinolysis. Intravenous administration of TRH and digipramine increased the procoagulant activity of the blood and thrombocyte aggregation but decreased fibrinolysis; digipramine had a more pronounced effect on the coagulation potential of the blood and a less pronounced effect on fibrinolytic indices as compared to TRH. Intranasal administration of the peptides did not change the pattern of their effect on hemostatic indices although the effects became less pronounced.

[Effects of neurohypophysial hormones and their synthetic analogs on platelet aggregation]. / Vliianie neirogipofizarnykh gormonov i ikh sinteticheskikh analogov na agregatsiiu trombotsitov.

The effect of neurohypophysial hormones vasopressin and oxytocin as well as their synthetic analogs on platelet aggregation induced by thrombin or ADP was studied in vitro on washed rat platelets. Vasopressin and its analog DGAVP, as well as oxytocin enhanced thrombin-induced platelet aggregation, while their effect on ADP-induced aggregation was considerably lower. An oxytocin analog depotocin had a pronounced antithrombin effect indicated by a significant inhibition (by 81%) of thrombin-induced platelet aggregation and by assay for its antithrombin activity in the blood plasma.

[The effect of modified forms of vasopressin on the rat hemostatic system]. / Vliianie modifitsirovannykh form vazopressina na sistemu gemostaza krys.

The effect of modified forms of vasopressin (MFV) that do not possess hormonal activity on homeostasis in rats was studied. One of the major effects of vasopressin (AVP) and its analogs on the blood clotting system, changes in fibrinolytic activity (FA) and the activity of plasminogen activator (APA), depends on modifications of the amino acid sequence in the peptide molecule. The presence of glycinamide in the AVP molecule enhances FA and APA. AVP molecules without the glycinamide group exert a more marked influence on procoagulant activity in blood.