Effects of thrombin, PAR-1 activating peptide and a PAR-1 antagonist on umbilical artery resistance in vitro

Human umbilical artery samples were obtained from 17 women at term. Arterial rings were suspended under physiologic conditions for isometric recording. The in vitro effects of thrombin (0.5 units/mL to 3 units/mL), PAR1-AP TFLLR-NH2 [10(-9) to 10(-6) M], and PAR-1 antagonist (N-trans cinnamoyl- p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Orn-NH2) [10(-9) M to 10(-5) M] on umbilical artery tone were measured.Both thrombin and TFLLR-NH2 exerted a potent cumulative vasodilatory effect on human umbilical artery resistance (P < 0.001). The mean net maximal inhibition (MMI) for thrombin was 53.05% (n = 6; SEM = 1.43) at tissue bath concentration of 3 units/mL. The MMI with TFLLR-NH2 was 61.50 % (n = 6; SEM = 1.43) at bath concentration of 10(-6) M. In comparison to vehicle control, the PAR-1 antagonist did not show a significant relaxant or contractile effect (P > 0.05).These findings highlight a potential role for thrombin and PAR-1 receptors in vascular regulation of feto-placental blood flow in normal pregnancy, and in association with the vascular lesions associated with IUGR and pre-eclampsia.In disorders resulting in poor fetal growth, and in pre-eclampsia, thrombotic lesions are frequently observed in the maternal and fetal vascular components of the placenta, [1-3] and hence have been implicated in the pathophysiology of these conditions. In addition, it has been reported that in vivo generation of thrombin, in maternal plasma, is higher in patients with small for gestation age fetuses and with pre-eclampsia, than in normal pregnancy [4]. It is well established, for many years, that thrombin plays a role in blood coagulation, but its effects in many other cell and tissue types (smooth muscle cells, endothelial cells, lymphocytes) [5,6] have been the subject of more recent attention. It is now apparent that thrombin can regulate target cells by cleaving and activating a family of G-protein-coupled protease-activated receptors (PARs)[5-7]. This proteolytic cleavage of PARs i