Abstract 1030: F 16618, A Novel Selective PAR1 Antagonist In The Prevention Of Vasoconstriction And Restenosis
F 16618 is a new phenyl-pentadienoyl derivative which competitively antagonizes PAR1 giving a prevention in vitro against human platelet aggregation. Beside its effects on platelet function, antagonism of PAR1 may reduce vasoconstriction and may prevent restenosis during the chronic reperfusion of coronary atherosclerotic arteries. Therefore, the aim of the present study was to evaluate the vascular effects of F 16618. Firstly, the effects of F 16618 (from 10 nM to 10 μM) were evaluated on endothelium denuded rat carotid rings suspended in organ baths containing Krebs solution maintained at 37 °C and bubbled with 95% O2/5% CO2. In these conditions, SFLLR, a PAR1 agonist, induced a concentration-dependant constriction with an EC50 of 8.4 μM. F 16618 antagonized the SFLLR-induced denuded rat carotid contraction in a competitive manner with a pA2 of 7.7. Secondly, the effects of F 16618 were examined in a vascular restenosis model involving balloon angioplasty in rats. A Fogarty arterial embolectomy balloon catheter was inserted into the left carotid artery. The degree of neointimal thickening was expressed as neointima area to media area ratio (N/M). Curative oral administration during the 14 days following injury (40 mg/kg p.o. once a day) significantly reduced neointimal thickness (N/M ratio: 1.35 ± 0.17 in the vehicle vs 0.74 ± 0.13 in the presence of F 16618, n=5) clearly demonstrating an important role for PAR1 in vascular injury. From these results, it is clear that F 16618, a potent PAR1 antagonist, is not only effective for treating platelet-dependent thrombosis, but also, could be beneficial for treating vasoconstriction and restenosis attendant to arterial injury.