Impaired feedback regulation of the receptor activity and the myofilament Ca2+ sensitivity contributes to increased vascular reactiveness after subarachnoid hemorrhage
Impaired feedback regulation of the receptor activity and the myofilament Ca2+ sensitivity contributes to increased vascular reactiveness after subarachnoid hemorrhage
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DOI：
10.1038/jcbfm.2010.35
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发表时间：
2010-09-01
影响因子：
6.3
通讯作者：
Hirano, Katsuya
中科院分区：
文献类型：
--
作者：
Kikkawa, Yuichiro;Kameda, Katsuharu;Hirano, Katsuya
脑血管痉挛决定了蛛网膜下腔出血（SAH）的预后。血管反应性增加在脑血管痉挛的发生发展中起重要作用。本研究分析了受体介导的信号传导和肌丝Ca 2+敏感性在SAH血管反应性增加中的作用，使用兔SAH模型的基底动脉。内皮素-1、凝血酶和苯肾上腺素诱导[Ca 2 +]（i）、肌球蛋白轻链磷酸化和对照组收缩的瞬时增加。所有这些反应在SAH中不仅增强，而且变得持续。在凝血酶受体或α 1肾上腺素受体的顺序刺激中，对照组的第二反应明显减弱，而SAH组的第二反应得以维持。在SAH中，凝血酶诱导的收缩不可逆地持续，即使在终止凝血酶刺激后。这种收缩被胰蛋白酶和G（α q）抑制剂YM 254890完全逆转，从而表明在持续收缩期间持续的受体活性。YM 254890还抑制内皮素-1和苯肾上腺素诱导的持续收缩。此外，在对照α-毒素透化条中GTP γ S诱导的短暂收缩在SAH中转化为持续收缩。结果首次证明SAH中受体活性的反馈失活和肌丝Ca ~（2+）敏感性受损，从而导致血管反应性增加。Journal of Cerebral Blood Flow & Metabolism（2010）30，1637-1650; doi：10.1038/jcbfm.2010.35; 2010年3月17日在线发表
Cerebral vasospasm determines the prognosis of subarachnoid hemorrhage (SAH). The increased vascular reactiveness has an important role in the development of cerebral vasospasm. This study analyzed the roles of the receptor-mediated signaling and the myofilament Ca2+ sensitivity in the increased vascular reactiveness in SAH, using the basilar artery of a rabbit SAH model. Endothelin-1, thrombin, and phenylephrine induced transient increases in [Ca2+](i), myosin light chain phosphorylation, and contraction in the controls. All these responses were not only enhanced but also became sustained in SAH. In the sequential stimulation of thrombin receptor or alpha(1)-adrenoceptor, the second response was substantially attenuated in the controls, whereas it was maintained in SAH. The thrombin-induced contraction in SAH irreversibly persisted even after terminating the thrombin stimulation. This contraction was completely reversed by trypsin and a G(alpha q) inhibitor YM254890, thus suggesting the sustained receptor activity during the sustained contraction. YM254890 also inhibited the endothelin-1- and phenylephrine-induced sustained contraction. Furthermore, the GTP gamma S-induced transient contraction in the control alpha-toxin-permeabilized strips was converted to a sustained contraction in SAH. The results provide the first evidence that the feedback inactivation of the receptor activity and the myofilament Ca2+ sensitivity was impaired in SAH, thus contributing to the increased vascular reactiveness. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1637-1650; doi:10.1038/jcbfm.2010.35; published online 17 March 2010