Abstract Number: PB0144
Meeting: ISTH 2020 Congress
Background: Carvedilol is a β-adrenoceptor antagonist of β1 and β2 receptors and a competitive antagonist of α1-adrenoreceptor. There are data that carvedilol exerts antithrombotic activity in extracorporeal circulation, probably due to its metabolites, which act as a β2-adrenoreceptor agonists.
Aims: The aim of the study was to evaluate antithrombotic properties of carvedilol and its metabolites by the use of two different intravital real time thrombosis models: laser induced thrombosis and ferric chloride induced thrombosis.
Methods: The mesenteric vascular bed of C57BL/6-Tg(CAG-EGFP)1Osb/J transgenic mice was exposed after making a midline laparotomy incision. For intravital fluorescence, confocal microscopy of the microcirculation of a living mouse, carvedilol was administered p.o. at doses of 3 and 10 mg/kg. To assess possible involvement of β-receptors in antithrombotic effect of carvedilol, atenolol (10mg/kg,.) and labetalol (30mg/kg) was used. We inhibited metabolism of carvedilol with ketoconazole (50mg/kg) or 1-aminobenzotriazole (1-ABT,200 mg/kg). Platelet accumulation in the blood vessel at the site of thermal laser injury or chemical ferric chloride injury of endothelium was measured as an area of fluorescence which is corresponding to the thrombus volume.
Results: Carvedilol significantly decreases platelet accumulation at the site of endothelial injury. Atenolol, labetalol, ketokonazole and 1-ABT does not exert antiplatelet effect when administered alone. Furthermore, platelet accumulation was reversed by labetalol and ketoconazole.
Conclusions: Carvedilol exerts antithrombotic effect due to inhibition of platelet accumulation by various mechanisms. On the one hand, this effect is not-dependent to β-1 adrenoceptor (atenolol study) and not-dependent to CYP2D6 (1-ABT study). On the other hand, study with ketoconazole revealed that this effect is dependent on CYP3A4 metabolites of carvedilol and labetalol (receptor study). Summing up, carvedilol seems to be very attractive drug alternative in cardiovascular states complicated with thrombosis. Further experiments under individual carvedilol metabolites are planned.
To cite this abstract in AMA style:Czajkowski P, Jarmoc D, Rusak T, Kramkowski K. Antithrombotic Properties of Carvedilol Shown in Two Independent Intravital Real Time Models of Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/antithrombotic-properties-of-carvedilol-shown-in-two-independent-intravital-real-time-models-of-thrombosis/. Accessed May 6, 2021.
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