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

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 ^-1, 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 ^-1. The contractile response to PAR ₁-activating peptide was also enhanced after SAH. However, the contractile responses to high K ⁺ and endothelin-1, and the myofilament Ca ²⁺-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.