Up‐regulation of proteinase‐activated receptor 1 and increased contractile responses to thrombin after subarachnoid haemorrhage

Abstract

Background and purpose: The mechanism for the development of post-haemorrhagic cerebral vasospasm after subarachnoid haemorrhage (SAH) still remains unknown. Experimental approach: We investigated the role of thrombin and its receptor PAR 1 in the development of hyper-contractility of the basilar artery in a rabbit double haemorrhage model, which received two injections of autologous blood into the cisterna magna. Key results: In the basilar artery isolated from the control rabbits, thrombin, only at 10 units ml À1 , induced a transient endothelium-dependent relaxation and a slight smooth muscle contraction. In SAH, the contractile response to thrombin was markedly enhanced, while the endothelium-dependent relaxant effect of thrombin remained unchanged. The enhancement of the contractile responses was also observed in the absence of endothelium and thrombin induced an enhanced contraction at concentrations higher than 0.3 units ml À1 . The contractile response to PAR 1 -activating peptide was also enhanced after SAH. However, the contractile responses to high K þ and endothelin-1, and the myofilament Ca 2 þ -sensitivity remained unchanged after SAH. An immunoblot analysis suggested the up-regulation of PAR 1 in the smooth muscle of the basilar artery. The heparinization of blood before injection prevented the enhancement of the contractile responses to thrombin and PAR 1 -activating peptide. Conclusions and implications:The present study demonstrated, for the first time, that the contractile response of the basilar artery to thrombin was markedly enhanced after SAH. Mechanistically, our findings suggested that the activation of thrombin following hemorrhage up-regulated the expression of PAR 1 , thereby inducing the hyper-responsiveness to thrombin.

Impaired Feedback Regulation of the Receptor Activity and the Myofilament Ca2+ Sensitivity Contributes to Increased Vascular Reactiveness after Subarachnoid Hemorrhage

“…This study showed the upregulation of receptors for all these agonists in SAH. The upregulation of ET A receptor and PAR 1 is consistent with the observations of the previous reports (Ide et al, 1989;Itoh et al, 1994;Maeda et al, 2007;Vatter et al, 2007), whereas no study has previously reported the upregulation of a 1 -adrenoceptor in SAH. The upregulation of PAR 1 and a 1 -adrenoceptor may be consistent with the enhancement of the maximal response.…”

“…The general impairment of the receptor inactivation may be consistent with previous reports showing the enhanced contractile response to various receptor ligands (Hansen-Schwartz et al, 2003;Itoh et al, 1994;Kai et al, 2007;Kai et al, 2008;Maeda et al, 2009;Maeda et al, 2007;Vatter et al, 2007). However, the impaired receptor inactivation exerts a significant effect especially on the activity of ET A receptor and PAR 1 .…”

Current Perspective on the Role of the Thrombin Receptor in Cerebral Vasospasm After Subarachnoid Hemorrhage

“…In the basilar artery of the control animals, the contractions induced by thrombin, PAR 1 -AP, endothelin, and phenylephrine gradually decreased after reaching the maximal level of contraction (Fig. 1B) (22,24). However, after SAH, the contractile response to these agonists was not only enhanced as mentioned above, but also prolonged (Fig.…”

“…In contrast, in the basilar artery isolated from the SAH model animals, thrombin induced a significantly enhanced contraction at lower concentrations (22 -24). The enhanced reactivity was also observed with a agonist peptide for proteinase-activated receptor (PAR) 1 (PAR 1 -AP), but not for PAR 4 (PAR 4 -AP), thus suggesting that PAR 1 is a major receptor mediating the contractile effect of thrombin after SAH (22,23). Similar enhancement of the reactivity was also observed with platelet-derived growth factor, an α-adrenoceptor agonist, and endothelin-1, but not for high K + -depolarization or phorbol ester (24,25).…”

Inhibitory Effects of the Dual Endothelin Receptor Blocker Bosentan on Thrombin-Activated Lung Fibroblasts Isolated from Scleroderma Patients

“…Previously, we demonstrated that thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the PAR-1 receptor and via a PKC-dependent pathway [6]. Thrombin is known to induce ET-1 in various cell types [12,13]. Moreover, ET-1 and thrombin have similar pro-fibrogenic effects in lung fibroblasts and endothelial cells [14][15][16].…”