Triflavin Inhibits Platelet-Induced Vasoconstriction in De-endothelialized Aorta

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Abstract
Triflavin, a 7.5-kD cysteine-rich polypeptide purified fromTrimeresurus favoviridissnake venom, belongs to a family of Arg-Gly-Asp-(RGD)–containing peptides, termed disintegrins. In this study, aggregating human platelets dose- dependently induced vasoconstriction in de-endothelialized isolated rat thoracic aortas. At 5×107cells per milliliter, platelets induced a peak tension averaging 65±7.2% of the tension induced by phenylephrine (10 μmol/L). The relative effectiveness of RGD-containing peptides (including venom peptides triflavin and trigramin, small RGD synthetic peptides Gly-Arg-Gly-Asp-Ser [GRGDS], Gly-Arg-Gly-Asp-Phe [GRGDF], and Gly-Arg-Gly-Asp-Ser-Pro-Lys [GRGDSPK]) was examined by testing the inhibitory effect on aggregating platelet-induced vasoconstriction in de-endothelialized aorta. Triflavin (1 μmol/L) significantly inhibited the platelet-induced vasoconstriction, whereas neither trigramin (10 μmol/L) nor small RGD peptides (2 mmol/L) (ie, GRGDS, GRGDF, and GRGDSPK) showed any significant effect. The release of serotonin and the formation of thromboxane A2from aggregating platelets were both significantly inhibited by triflavin (2 μmol/L), whereas trigramin and small RGD-containing peptides showed no significant effect. On scanning electron micrographs of de-endothelialized aorta, aggregating platelets adhered to the subendothelium, with loss of their discoid shape, to form irregular spheres with pseudopod extensions. Triflavin (2 μmol/L) markedly reduced the adhesion of platelets to the subendothelium in the same aorta. Furthermore, RGD-containing peptides (including triflavin, trigramin, and small RGD-containing peptides) inhibited the adhesion of 10 μg/mL collagen-activated platelets to extracellular matrices (ie, fibronectin, vitronectin, and von Willebrand factor). It is concluded that the marked ability of triflavin to inhibit aggregating platelet-induced vasoconstriction in de-endothelialized aorta compared with other RGD-containing peptides (including trigramin), may be due at least partly to triflavin’s efficiently preventing the activation of platelets subsequent to inhibition of serotonin release and thromboxane A2formation. However, the different abilities of triflavin compared with other RGD-containing peptides was not related to the ability to inhibit adhesion of platelets to extracellular matrices. Therefore, from the results of this study, it appears that triflavin may be a useful therapeutic agent for the treatment of thromboembolism and its associated angiospasm.

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