Abstract
BackgroundThe non-thrombotic effects of thrombin in cardiovascular tissues, as mediated via the protease activated receptors (PARs), and particularly PAR-1, have been the focus of much recent research. The aims of this study were to evaluate the effects of thrombin, a specific PAR-1 activating peptide (PAR1-AP), and a PAR-1 antagonist on human umbilical artery tone in vitro.MethodsHuman 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.ResultsBoth 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).ConclusionThese 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.
Highlights
The non-thrombotic effects of thrombin in cardiovascular tissues, as mediated via the protease activated receptors (PARs), and PAR-1, have been the focus of much recent research
Reproductive Biology and Endocrinology 2005, 3:8 http://www.rbej.com/content/3/1/8 plays a role in blood coagulation, but its effects in many other cell and tissue types [5,6] have been the subject of more recent attention
The aims of this study were to evaluate the direct effects of thrombin, the specific PAR-1 activating peptide (PAR1-AP), TFLLR-NH2 (Thr-Phe-Leu-LeuArg-NH2), and the PAR-1 specific antagonist (N-trans cinnamoyl -p-fluoroPhe-p-quanidinoPhe-Leu-Arg-OrnNH2) on human umbilical artery tone in vitro
Summary
The non-thrombotic effects of thrombin in cardiovascular tissues, as mediated via the protease activated receptors (PARs), and PAR-1, have been the focus of much recent research. 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 (page number not for citation purposes). It is apparent that thrombin can regulate target cells by cleaving and activating a family of G-protein-coupled protease-activated receptors (PARs)[5,6,7]. PAR-1, PAR-3 and PAR-4 [11] are all known to be thrombin receptors, the mechanism of activation by thrombin at these different PARs varies [12,13]
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