Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage.

Abstract

BACKGROUND AND PURPOSE: Cerebral vasospasm is one of the major complications of subarachnoid hemorrhage (SAH). Its pathogenesis still remains elusive, and effective therapeutic strategies are yet to be established. We investigated the role of proteinase-activated receptor-1 (PAR1) in the hypercontractile state in SAH. METHODS: Rabbit double hemorrhage model was used as a model of SAH. The contractile response to thrombin and the PAR1 expression were evaluated in the isolated rings of basilar artery. RESULTS: Thrombin exhibited only a minor contractile effect in the control, whereas it induced augmented contractions in SAH. The expression of PAR1 was upregulated in SAH. Intracisternal injection of PAR1 antagonist E5555 prevented the enhancement of the contractile responses to thrombin in SAH. The maximal prevention was obtained with 2 microg/kg weight/injection. The contractile responses to K(+) depolarization or endothelin-1 remained unaffected. The upregulation of PAR1 was also prevented by E5555 (2 microg/kg weight/injection) to a level similar to that seen in the control. Ex vivo treatment with E5555 (1 micromol/L) inhibited the contraction induced by thrombin, whereas it had little effect on the contraction induced by K(+) depolarization or endothelin-1, in the basilar artery of SAH. E5555 also inhibited the [Ca(2+)](i) elevation induced by thrombin, but not trypsin, in cultured smooth muscle cells. CONCLUSIONS: PAR1 plays a critical role in upregulating PAR1 itself, thereby enhancing the contractile response to thrombin in SAH. PAR1 could thus be a therapeutic target. However, the usefulness of PAR1 antagonist remains to be investigated in vivo.