Ca^<2+> sensitization and deficiency of myosin light chain dephosphorylation in the pathogenesis of cerebral vasospasm

蛛网膜下腔出血(SAH)后脑血管痉挛的发病机制已被深入研究，但仍不完全清楚。脑血管痉挛与多种细胞内信号转导通路的活性改变有关，其中包括小GTP酶、Rho A和Rho-Kinase的激活。Rho A激活Rho-Kinase导致肌球蛋白磷酸酶复合体的肌球蛋白结合亚单位磷酸化，从而导致肌球蛋白磷酸酶失活。因此，小G蛋白信号的刺激导致脑动脉持续收缩，而不改变[Ca^&lt；2+&gt；]i，这可能是脑血管痉挛的病理生理机制之一。然而，关于钙敏化和脑血管痉挛之间关系的系统评估一直是缺乏的。首先，我们同时记录了犬基底动脉等长张力和细胞内钙离子浓度，几种激动剂通过钙增敏机制和Rho/Rho激酶途径收缩脑血管。其次，我们同步记录了实验性蛛网膜下腔出血模型犬基底动脉的等长张力和细胞内钙离子浓度。观察到痉挛的基底动脉对Ca~(2+)和Gt~(2+)的敏化程度有增加的趋势。另一方面，我们参加了一种生物活性分子，鞘氨醇-1-磷酸(S1P)，它可以从血小板中释放出来，刺激Rho/Rho-Kinase系统。我们探讨了S1P是否被认为是参与SAH后脑血管痉挛的一种新的痉挛物质。

The pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) has been intensively investigated but is not still fully understood. Cerebral vasospasm is associated with changes in the activity of several intracellular signal transduction pathways including the activation of small GTPase Rho A and Rho-kinase. Activation of Rho-kinase by Rho A causes phosphorylation of the myosin-binding subunit of myosin phosphatase complex, which leads to the inactivation of myosin phosphatase. Thus, the stimulation of small G-protein signaling results in the continuous contraction of cerebral arteries without changes in [Ca^<2+>]i, which may be responsible for the pathophysiology of cerebral vasospasm. However, the systemic assessment of relationship Ca^<2+> sensitization and cerebral vasospasm has been lacked previously. First we recorded simultaneously isometric tension and intracellular Ca^<2+> concentration in basilar artery from dogs, and several agonists contract cerebral vessels through Ca^<2+> sensitization mechanism and Rho/Rho kinase pathway. Second, we recorded simultaneously isometric tension and intracellular Ca^<2+> concentration in basilar artery from experimental SAH model dogs. The tendency of increasing Ca^<2+> sensitization in spastic basilar arteries was observed. On the other hand, we attended a bioactive molecule, sphingosine-1-phosphate (S1P) that can be released from platelets and stimulates Rho/Rho-kinase system. We investigated whether or not S1P is considered as a novel spasmogenic substance involved in the cerebral vasospasm after SAH.