[Modern views of the role of heparin in hemostasis and regulation of enzymatic and hormonal activities].

This review is focused on the role of heparin in the maintenance of hematological homeostasis. Description of the main components of the hemostatic system is presented. The mechanism of heparin action as an anticoagulating and fibrinolytic agent are analyzed. A hypothesis is forwarded to explain the role of heparin in animals and humans as a key substance promoting stabilization, regulation and distribution of different active blood components bound into complexes with heparin.

[Mast cells and heparin--key links in adaptive and pathological processes].

Participation of mast cells and heparin in adaptive and pathological processes is discussed with special reference to heparin pool in mast cell granules. Hypotheses explaining conversion of normal mast cells to phenotypically pathologic ones are analysed. Prospects for enhancement of adaptive abilities of the organism and approaches to the treatment of diseased organs are discussed in terms of protection and restoration of heparin cells in the mast cells.

[Problem of controls in physiology and pharmacology: psychophysiological and morphofunctional effects of chronic saline administration].

The psychophysiological and morphofunctional effects of chronic administration of saline, which is commonly used as an active control, to Wistar rats were analyzed at different levels. The active control proved to be complicated by signs of stress manifested as increased corticosterone levels, changes in the homeostatic system, blood cytometric indices, morphofunctional states of the thymus and spleen, sharp suppression of the cognitive activity, and decrease in the motivational and locomotor activities. Pain expectation developed in animals after the second saline injection in the tail-flick test--pain sensitivity sharply increased in the session prior to the injection. These signs of stress should be taken into account for interpretation of the effects in drug tests.

[Effects of stress agents and heparin administration on hematological parameters in Wistar rats]. / Gematologicheskie parametry u krys linii Vistar pri vozdeistvii stressornykh agentov i vvedenii geparina.

In chronic experiments in Wistar rats, the behavioral and hematological effects of the following stress factors were investigated: learning in complex maze and five multiple injections of the physiological saline (0.85%). Increasing of the erythrocyte volume and the contents of hemoglobin per erythrocyte in saline-induced groups and naive rats were observed after the learning. Moreover, the level of corticosterone in plasma of these rats was high. While in heparin-pretreated animals (unfractioned heparin, 64 and 640 IU/kg once per day, i.m., 5 days) these markers of stress are not revealed. The speed and efficiency of learning, behavior organization were significantly better in heparin pretreated rats than in naive and saline-induced groups. In heparin treated rats, a few types of unconditioned responses may be observed suggesting an anxiety or fear. We suppose that, after injections of heparin, complicated biochemical modifications of the rat organism that cause harmonization of inhibiting and excitatory processes of central nervous system, take place.

[Features of active control used in pharmacological studies]. / Osobennosti aktivnogo kontrolia, ispol'zuemogo v farmakologicheskikh issledovaniiakh.

The effects of 5 injections of salt solution and unfractionary heparin in dose 0.36 microgram/kg (Serva, Germany 10 kDa, activity 180 U/mg) have been studied in Wistar rats. It was found that two injections of salt solution were enough to form a stable defensive state in all rats which was manifested as an expectation of pain in tail-flick testing. The defensive motivation provoked by the injections negatively influenced the learning process as saline-induced rats refused to solve a food-getting task in a problem situation. Explorative and locomotor activities were depressed in these rats and were accompanied by numerous stressful and neurotic-like manifestations. Unlike saline-rats, practically all heparinized-rats instead of 45% of intact rats were able to solve a cognitive task despite the injections. Anxiety was decreased, but sensitivity to different external factors was increased in the heparin-induced rats. Formed habit in these rats was characterized by a high organization and stability. However, the majority heparin effects in tail-flick test were discovered when comparing the heparin-induced rats with intact ones and were not observed in comparison with the saline-rats. It is suggested that the saline-control should be considered as specific control having defensive features which are necessary to take into account in interpretation of effects of other pharmacological preparations.

[Psychostimulation of Wistar rats after intraperitoneal administration of high-molecular heparin]. / Psikhostimuliruiushchie éffekty vysokomolekuliarnogo geparina pri vnutribriushinnom vvedenii krysam linii Vistar.

The influence of repeated administration of heparin in learning was studied in Wistar rats (n = 20). High-molecular heparin (Serva, Germany, 10 kDa, activity of 180 IU/mg) was intraperitoneally injected daily in the dose of 64 IU/kg in a volume of 0.3 ml during 5 days prior to 4-link freechoice operant conditioning in a complex maze. As distinct from 40% of control rats, practically all heparin-treated rats were successful in conditioning. Parameters such as rate and efficiency of learning, behavior organization, habit stability, and extinction of errors were significantly better than in control animals. Anxiety was decreased, but sensitivity to external factors was increased in comparison with the control rats. The data obtained suggest that prior treatment with high-molecular heparin has a strong psychostimulant effect through activation of biogenic amines and formation of complexes with them.

[Comparative study of anticoagulants obtained from various extracts of Paeonia anomala]. / Sravnitel'nye issledovaniia antikoagulantov iz razlichnykh ékstraktov Paeonia anomalia.

We have established that extracts prepared from various parts of the root of Paeonia anomala (bark and wood) have anticoagulant activity as indicated by the criterion of longer recalcification time of the normal rat blood plasma. This anticoagulant activity is due to the presence of heparin-like fragments in the preparations, which follows from the results of biochemical analysis and results of studies on the functional state of the mast cell population. Preparations from the peony root bark retain their anticoagulant properties in the circulatory system for 1.5 h after intravenous administration, similarly to heparin of the animal origin.

[Various aspects of the effect of heparin-serotonin complex on blood and blood flow]. / Nekotorye aspekty deistviia kompleksa geparin-serotonin na krov' i krovotok.

High-molecular heparin-serotonin complex (3:1 weight ratio) was obtained in vitro. The complex, its components, and heparin-serotonin mixture were introduced intraperitoneally in rats, and the resulting effects were registered 10, 30, and 60 min later. The complex had anticoagulant and lytic activities distinct from those of plasmin. According to decrease activity of factor XIII and decreased concentration of fibrinogen, the complex stimulated the anticoagulant system. In addition, the heparin-serotonin complex penetrated the hematoencephalic barrier and decreased the rate of brain bloodstream. The observed physiological properties of the heparin-serotonin complex were distinct from those of serotonin, heparin, and their mixture.

[Heparin-piracetam complex and its effect on blood and blood circulation]. / Kompleks geparin-piratsetam, ego deistvie na krov' i krovotok.

High-molecular-weight heparin-piracetam complex (1:1 w/w ratio) was obtained in vitro. The complex, its components, or physiological solution were introduced intraperitoneally in rats (0.3 ml, 0.1%). Piracetam had no effect on homeostasis. The heparin-piracetam complex had a more pronounced anticoagulant and fibrinolytic activities than the individual components. In addition, this complex accelerated blood flow in the brain. In conditions of acute hypoxia (a 12,000-m altitude chamber), heparin protected animals from hypoxia more effectively than other substances.

[Low-molecular heparin complex formation with the blood coagulation proteins--thrombin and fibrinogen]. / Kompleksoobrazovanie nizkomolekuliarnogo geparina s belkami svertyvaniia krovi--trombinom i fibrinogenom.

It has been found that low molecular heparin (LMH) forms complexes with fibrinogen and thrombin. The formation of the heparin-fibrinogen and heparin-thrombin complexes has been testified by cross-linked electrophoresis. The reaction of complex formation was carried out at variable weight ratios of the components, i.e. 1:3 and 1:6, respectively. This complex causes lysis of unstabilized clots of fibrin. All these complexes manifested a slight anticoagulative activity.

[Fibrinolytic complexes of low-molecular heparin and acetylsalicylic acid]. / Fibrinoliticheskie kompleksy nizkomolekuliarnogo geparina s atsetilsalitsilovoi kislotoi.

Complexes of low-molecular heparin with acetylsalicilic acid was formed in vitro when the weight ratio of components was 1:1, 1:5 and 5:1, respectively. All the complexes possessed fibrinolytic and anticoagulating activities. The complex possessed the highest activity when the ratio of heparin to acetylsalicilic acid was 5:1. This complex at a dose 1 mg/200 g of rat weight had the largest thrombolytic effect on the experimental fresh thrombus.

[Interaction of heparin with defensin, a nonenzymatic cationic protein from neutrophils]. / Vzaimodeistvie geparina s nefermentnym kationnym belkom iz neitrofilov defensinom.

Heparin was shown to form complexes with cation non-enzymatic protein defensin from neutrophils. The complex obtained in vitro did not affect the anticoagulation and fibrinolytic properties of blood, whereas defensin decreased the content of heparin, rates of non-enzymatic fibrinolysis and total fibrinolytic activity while heparin stimulated the anticoagulation activity of blood plasma. Interaction of heparin with defensin appears to be involved in protective mechanism responsible for neutralization of both the heparin anticoagulation activity and the defensin properties related to inhibition of nonenzymatic fibrinolysis.

[A comparative study of the action of preparations of high- and low-molecular weight heparin on hemostatic indices in vitro and in their intravenous administration to animals]. / Sravnitel'noe izuchenie deistviia preparatov vysoko- i nizkomolekuliarnogo geparina na nekotorye pokazateli gemostaza in vitro i pri vnutrivennom vvedenii zhivotnym.

Low-molecular heparin preparations (a Soviet sample and that manufactured by the Celsus Company) in vitro, added to bovine plasma possess a lower antifactor-II activity, less time of recalcification and partial thromboplastin time as compared to high-molecular heparin of equal concentration (mg/ml) or dose (Units/ml). After intravenous injection of low-molecular heparin preparations to animals in a dose of 50 Units/200 g bw the time of hemorrhage was far less, while anticoagulant activity was lower than in animals given the same dose of high-molecular heparin. Both injection of low-molecular and high-molecular heparin results in a rise of the intensity of non-enzymatic fibrinolysis in the animals' blood plasma.

[The blood anticoagulant system in rats perorally administered a heparin-acetylsalicylic acid complex]. / Sostoianie protivosvertyvaiushchei sistemy krovi krys pri peroral'nom vvedenii kompleksa geparin--atsetilsalitsilovaia kislota.

Heparin/acetylsalicylate complexes (1:9 and 10:1) were obtained in vitro. Single or chronic (7-8 days) per os administration to white rats of 0.1% solution of the heparin/acetylsalicylate complex (0.3 ml/200 g body weight) enhanced anticoagulative properties of blood plasma, increased the fibrinolytic activity in respect of stabilized fibrin, and diminished the thrombin-induced platelet aggregation.

[Process of fibrin depolymerization and non-enzymatic fibrinolysis in rabbits receiving atherogenic rations with addition of antioxidants]. / Protsess depolimerizatsii fibrina i nefermentativnyi fibrinoliz u krolikov, poluchaiushchikh aterogennyi ratsion s dobavleniem antioksidantov.

The rabbits were kept on atherogenic ration for 2 months. This diet contained 0.3 mg/kg of cholesterol. In blood plasma of animals the authors observed a sharply reduced non-enzymatic fibrinolysis and depolymerization activity of non-stabilized fibrin. The addition of antioxidants and alpha-tocopherol (10 + 10 mg/kg) for 1 month to the atherogenic ration protected from the disturbance of the system hemostasis and normalized the depolymerization of non-stabilized fibrin.