Abstract 883: A Novel Strategy to Prevent the Vasospastic Response of the Basilar artery to Thrombin in Subarachnoid Hemorrhage Using a Selective Proteinase-Activated Receptor-1 Antagonist
Cerebral vasospasm is one of the major complications of subarachnoid hemorrhage (SAH). However, its pathogenesis still remains to be elucidated, and effective therapeutic strategies are yet to be established. We have reported, in the previous meeting, that thrombin plays a key role in up-regulation of the proteinase-activated receptor-1 (PAR1) expression and development of the vasospastic response to thrombin in the basilar artery of rabbit double hemorrhage-SAH model. In the present study, we demonstrated a new strategy to prevent the development of such vasospastic response using selective PAR1 antagonists. The rabbits received two injections of autologous blood into the cisterna magna on days 0 and 2. The contractile responses were examined on day 7 using basilar artery ring preparations, in the absence of endothelial cells. Thrombin and PAR1 activating peptide (PAR1-AP) slightly contracted the control artery only at high concentrations (10 U/ml thrombin or 100 μM PAR-1AP). In SAH, the contractile responses to thrombin and PAR1-AP were greatly enhanced, and also observed at lower concentrations than in the control. The activating peptides for PAR2 and PAR4 induced no contractile response. The contractile responses to high K+ depolarization or endothelin-1 seen in SAH did not significantly differ from those seen in the control. Western blotting revealed that PAR-1 expression of the basilar artery was up-regulated in SAH. When E5555 (2 μg/kg weight/injection), a novel PAR1 antagonist, was injected twice into the cisterna magna with autologous blood, enhancement of the contractile response to thrombin was almost completely inhibited, and the up-regulation of PAR-1 expression was prevented. We thus conclude that PAR1 plays a key role in the development of the vasospastic state of the cerebral artery in SAH. PAR1 antagonists may thus be useful as a new therapeutic strategy to prevent cerebral vasospasm in SAH.