In vitro comparison of physiological effects of PAR1 antagonist vorapaxar and parmodulin-2 on human left internal mammarian artery

Objective: The protease-activated receptor 1, an antiplatelet drug target, is expressed in vascular endothelial and smooth muscle cells as well as expressed in platelets. The effects of vorapaxar, the orthosteric protease-activated receptor 1 inhibitor and parmodulin-2, the bias agonist of protease-activated receptor 1, on the endothelial layer were evaluated in cell culture and vorapaxar has been suggested to cause endothelial damage. The aim of this thesis is to compare the effects of vorapaxar and parmodulin-2 on human left internal mammary artery responses in vitro. Method: Endothelial layer intact tissues were incubated with vorapaxar/ parmodulin-2 to determine endothelium-dependent relaxation response. Subsequently, endothelium-dependent relaxation response in the presence of L-NAME, L-arginine, indomethacin, caribdotoxin-apamine and protein C activator was investigated in addition to vorapaxar/ parmodulin-2 incubation. The effect of vorapaksar/parmodulin-2 on endothelium-independent relaxation response was evaluated with sodium nitruoprussite. The effect of vorapaxar/parmodulin-2 on the endothelial layer was imaged using a transmission electron microscope. Results: Vorapaxar has been found to cause statistically significant endothelial disfunction and is mainly caused by disrupting nitric oxide and endothelium-derived hyperpolarizing factor dependent relaxation mechanisms. In the presence of protein C activator, the effect of vorapaxar on endothelial function was prevented. Both molecules did not disrupt endothelium-independent relaxation responses. The effect of vorapaxar on the endothelial layer was supported by the images obtained by transmission electron microscope. Conclusion: As a result, parmodulin-2 may be a better option in cardiovascular diseases than vorapaxar because it inhibits protease-activated receptor 1 without disturbing the protective pathways of this receptor.