Antithrombotic Effects of Three Thrombin Inhibitors in a Rat Model of Laser-Induced Thrombosis

The effect of recombinant hirudin (r-hirudin; HBW 023) was studied in four different models of thrombosis as well as on bleeding time. Arteriolar thrombus formation was induced in rats either by argon laser injury or by photochemical reaction. r-Hirudin, given by intravenous infusion, significantly inhibited arteriolar thrombus formation and arterial bleeding time at a dose of 40 μg/kg·min. In rabbit jugular veins and carotid arteries, occluding thrombi were produced by stenosis and endothelial damage. r-Hirudin reduced the incidence of thrombosis dose dependently (ED50 0.7 and 1.0 mg/kg i.v. in arteries and veins, respectively). Caval vein thrombosis was initiated in rats by insertion of a stainless steel coil. This thrombosis was dose dependently reduced by the injection of r-hirudin (ED50 0.16 mg/kg i.v.). The duration of the antithrombotic effect of 0.25 mg/kg of r-hirudin in caval veins was about 60 min, whereas the arterial bleeding time was significantly prolonged in these rats for only 20 min. The plasma level of r-hirudin had dropped to 0.12 μg/ml 60 min after injection. These results suggest that the duration of the effect on bleeding time may be shorter than the antithrombotic action of r-hirudin.

Section: Discussionsupporting

confidence: 65%

Antithrombotic Effects of Recombinant Hirudin in Different Animal Models

Just¹,

Tripier²,

Seiffge³

1991

“…In contrast, Krupinski et al [8] studied rat mesenteric vessels using an argon laser model and reported that the antithrombotic effect of argatroban (0.5 mg/kg) lasted as long as 4 h. It seems likely that the differences between the present results and those of Krupinski et al [8] were due to the nature of the blood vessels and the type of laser used for the induction of thrombosis. Many properties of cerebral ves sels are known to be different from those of other vessels [ 1 -5], and studies by others have shown that thrombi generated with an argon laser are readily disrupted by flowing blood.…”

Section: Discussioncontrasting

confidence: 87%

“…The different proper ties of cerebral vessel walls from those of other blood vessels have been emphasized, for example the existence of a blood-brain bar rier, the appearances of intercellular junctions and the variable enzyme activities of endothe lial cells [1][2][3]. In addition, it has been re ported that thrombomodulin is absent from cerebral vessels [4,5], although this finding has been disputed [6], Models of thrombosis have been used for the assessment of the anti thrombotic effect of antiplatelet or anticoagu lating agents in several experimental animals using lasers and mesenteric blood vessels [7][8][9][10][11][12][13]. It is important to evaluate the effects of these agents on cerebral vessels.…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic Effect of Argatroban on the Pial Vessels of the Rat: A Study with He-Ne Laser-Induced Thrombus Formation

Sasaki

Morii

Yamashita

et al. 1993

The antithrombotic effect of the synthetic thrombin inhibitor (2R,4R)-4-methyl-1 -[N²-(3-methyl-1,2,3,4-tetrahydro-8-quin-olinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid mono-hydrate (argatroban) was investigated in cerebral vessels of the rat. An occlusive thrombus was formed in pial vessels using a He-Ne laser in a closed cranial window technique. Argatroban retarded the formation of thrombi in a dose-dependent manner. The antithrombotic effect of a single intravenous dose of argatroban at 0.5 mg/kg was diminished after 30 min in arterioles and after 50 min in venules, respectively. The antithrombotic activity was maintained, however, by continuous intravenous infusion (2 mg/kg/h).

“…The effective energy below the objective X 50 was adjusted to 0.12 W. The exposure times of the laser beam were 1/15 s. An intestinal loop exposed through a hypogastric incision and continuously irrigated with prewarmed (37 °C) saline was spread on a self-constructed device mounted on the microscope table. The laser beam was directed at small mesenteric venules (diameter 25-30 pm) in the fat-free portion of the mesentery [5][6][7]. Thrombus formation was evaluated by direct obser vation through the microscope.…”

Section: Methodsmentioning

confidence: 99%

Effects of Different Hirudins and Combinations of Low Doses of Hirudin, Heparin and Acetylsalicylic Acid in a Rat Microcirculatory Thrombosis Model

Krupiński

Breddin

1991

Self Cite

Two recombinant hirudins (r-hirudin), natural hirudin and hirudin in combination with heparin or acetylsalicylic acid (ASA) have been studied in a thrombosis model in which rat mesenteric venules of a diameter of 20–30 μm were injured by well-defined argon laser lesions. In the animal model all hirudins showed significant and dose-dependent antithrombotic effects in doses between 0.05 and 0.1 mg/kg after single intravenous and subcutaneous injections. The antithrombotic effect of single (0.2 mg/kg i.v. or 0.1 mg/kg s.c.) injections lasted longer than 4 h (i.v.) or 6 h (s.c). Hirudin at a dose of 0.1 mg/kg and heparin at doses of 0.05 mg/kg showed a significant antithrombotic effect 2 h after subcutaneous injection. When heparin and hirudin were injected together at this dosage, the effect of the combination was in the same range as that of unfractionated heparin or hirudin alone. An additive antithrombotic effect was observed if a low dose of r-hirudin (0.1 mg/kg) was combined with a moderate dose of ASA (10 mg/kg).