Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage
Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage
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DOI：
10.1161/strokeaha.107.487769
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发表时间：
2007-12-01
期刊：
影响因子：
8.3
通讯作者：
Kanaide, Hideo
中科院分区：
文献类型：
--
作者：
Kai, Yasutoshi;Hirano, Katsuya;Kanaide, Hideo
背景和目的：脑血管痉挛是蛛网膜下腔出血(SAH)的主要并发症之一。其发病机制仍不清楚，有效的治疗策略尚未建立。目的探讨蛋白酶激活受体-1(PAR1)在蛛网膜下腔出血(SAH)高收缩状态中的作用。在分离的基底动脉环上观察凝血酶的收缩反应和PAR1的表达。结果凝血酶在对照组仅表现出轻微的收缩作用，而对SAH则有增强的收缩作用。SAH组PAR1表达上调。蛛网膜下腔注射PAR1拮抗剂E5555可阻止SAH对凝血酶的收缩反应增强。预防效果最好的剂量为2 mg/kg体重/次。对K+去极化或内皮素-1的收缩反应不受影响。E5555(2微克/千克体重/注射)也可阻止PAR1的上调，达到与对照组相似的水平。E5555(1mU/L)可抑制凝血酶引起的基底动脉收缩，但对K+去极化或内皮素-1引起的收缩无明显影响。E5555还能抑制凝血酶引起的血管内皮细胞[Ca~(2+)](I)升高，但不能抑制胰酶引起的[Ca~(2+)](I)升高。结论PAR1在上调PAR1自身表达中起关键作用，从而增强SAH对凝血酶的收缩反应。因此，PAR1可能成为治疗的靶点。然而，PAR1拮抗剂的有效性仍有待于体内研究。
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 mu g/kg weight/injection. The contractile responses to K+ depolarization or endothelin-1 remained unaffected. The upregulation of PAR1 was also prevented by E5555 (2 mu g/ kg weight/injection) to a level similar to that seen in the control. Ex vivo treatment with E5555 (1 mu mol/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 [Ca2+](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.