Anticoagulant, fibrinolytic, and hypoglycemic effects of tetrapeptide Arg-Pro-Gly-Pro.

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.

[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.

[Regulatory role of heparin compounds with low molecular blood ligands in plasma and thrombocyte hemostasis].

Analysis 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.

[Fibrinolytic and hypoglycemic effects of the Pro-Gly-Pro-Leu peptide during development of insulin-dependent diabetes in rats].

Repeated (over 7 days) intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals at a dose of 1 mg/kg before injection of the diabetogenic metabolite alloxan provided effective protection of an organism against development of insulin-dependent diabetes mellitus and prevented development of hypercoagulating alterations in the system of hemostasis. An increasing in the anticoagulating and fibrinolytic activities in rat blood plasma was detected. The peptide under study also showed antidiabetogenic action: repeated intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals for 7 days inhibited development of diabetes symptoms in rats pretreated with alloxan.

[The protective effect of the arginine-heparin complex under simulation of insulin-dependent diabetes].

Daily intramuscular injections of the arginine-heparin complex for 5 days before injection of diabetogenic metabolite alloxan did not cause insulin-dependent diabetes in animals for 3 weeks. As a result of these injections, the anticoagulant fibrinolytic pattern of the anticoagulant system was activated and the platelet aggregation decreased. This effect held for 7 days after injection.

Anticoagulant effects of a complex of high molecular weight heparin and arginine.

Heparin forms a complex compound with arginine in a pure system, which was shown by biochemical methods. A method for obtaining the complex in vitro has been developed. At arginine/heparin molar ratio of 3:1 the complex exhibited anticoagulant, antiplatelet, and fibrin-depolymerization activities. High fibrin-depolymerization and anticoagulant activities were documented in the blood of animals 10 min after intravenous injection of the arginine-heparin complex, in contrast to the picture after injection of the complex components (heparin and arginine) alone.

[Antidiabetogenic action of Pro-Gly-Arg and Pro-Gly-Pro-Arg peptides after their intranasal chronic administration to animals].

It was shown that chronic (over 7 days) intranasal injection of the Pro-Gly-Arg tripeptide to rats in the dose 1 mg/kg before the injection of a diabetogenic dose of alloxan, promotes effective defense against development of insulin dependent diabetes mellitus. At the same time, the tetra-peptide Pro-Gly-Pro-Arg did not show a hypoglycemic affect during diabetes mellitus provocation. Administration of Pro-Gly-Arg and Pro-Gly-Pro-Arg peptides also activates anticoagulation potential.

[Comparative study of hemostatic properties of the complex and mixture of high molecular weight heparin and adenosine triphosphate].

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.

Changes in hemostatic parameters after intranasal administration of peptide Pro-Gly-Pro.

Anticoagulant activity, total and nonenzymatic fibrinolytic activity, and tissue plasminogen activator activity increased, while platelet aggregation and activity of factor XIIIa in rat blood plasma decreased over 3 h after single intranasal administration of proline-containing peptide Pro-Gly-Pro. Hemostatic parameters in rats 24 h after single administration of this peptide did not differ from the control level observed in animals receiving 0.85% NaCl.

Antithrombotic activity of heparin-ATP complex.

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.

Correction effect of ATP on platelet aggregation and blood coagulation in vitro and in the presence of circulating thrombin in rats.

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.

[Antiplatelet effect of adenosine triphosphate administration to animals under different experimental conditions].

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 anti-coagulant 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.

[Effect of chronic intramuscular administration of low molecular weight heparin-collagen complex on hemostatic indices and development of alloxan-induced diabetes].

Repeated intramuscular administration of low molecular weight heparin-collagen complex proved to increase fibrinolytic activity and to decrease platelet aggregation in the blood of rats (11 months) with depressed anticoagulant system. Administration of diabetogenic alloxan dose induced no diabetes mellitus in such animals.

[Comparison of anticoagulant effects of regulatory proline-containing oligopeptides. Specificity of glyprolines, semax, and selank and potential of their practical application].

Experimental and theoretical demonstration of different effect of certain regulatory peptides (RPs) on blood coagulation is available. The problem of the role of RPs in hemostatic processes becomes particularly significant since, first, the peptides are widespread in nature both in animal and plant tissues, second, there is a relationship between the peptide structure and function and, third, both natural and synthetic peptides are used in practical medicine to correct functions of some factors of the hemostatic system. Many peptide inhibitors of the primary and plasma hemostasis potentiating anticoagulant effects in the body have been described.

[Antidiabetic properties of high molecular weight heparin-adenosine triphosphate complex].

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.

[Hemostaseological description of the heparin-adenosine triphosphate (ATP) complex].

Biochemical methods confirmed the presence of the heparin-ATP complex. Acid sulfonate 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 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.

[Effect of the heparin-lysine complex on the hemostatic and insular systems]. / Vliianie kampleksa geparin-lizin na gemostaticheskuiu i insuliarnuiu sistemu.

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.

[Antidiabetic and anticoagulant properties of the heparin-glutamic acid complex]. / Antidiabetogennye i protivosvertyvaiushchie svoistva soedineniia geparina s glutaminovoi kislotoi.

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.

Prevention of thrombus formation with glyprolines on various models of prethrombotic state and thrombosis in rats.

Peroral administration of peptide Pro-Gly-Pro to 10-11-month-old rats with modeled prethrombotic state normalized functions of the anticoagulation system and produced a potent antiplatelet effect. Peroral administration of Pro-Gly peptide before provocation of thrombin generation and thrombus formation prevented death of animals from thrombosis. Experiments on rats with venous thrombosis induced by stasis and administration of thrombin showed that pretreatment with Pro-Gly peptide decreased the weight of formed thrombi.