期刊
STROKE
卷 31, 期 2, 页码 526-533出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.STR.31.2.526
关键词
cerebral vasospasm; endothelins; protein kinases; rabbits
Background and Purpose-Endothelin-1 (ET-1) is suggested to be a major cause of cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1-induced contraction in cerebral arteries remains unclear. This study was undertaken to demonstrate the possible role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-l-induced contraction. Methods-PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET-1-induced contraction of basilar artery, studied with an isometric tension system. Immunoprecipitation of MAPK in ET-1-stimultated rings of basilar artery without or with the above inhibitors was studied with Western blot. Results-(1) ET-1 produced concentration-dependent contraction and MAPK immunoprecipitation in rabbit basilar artery by activation of ETA but not ETB receptors. (2) MAPK inhibitors PD-98059 and U-0126 produced dose-dependent inhibition of ET-1-induced contraction. (3) The Src tyrosine kinase inhibitor damnacanthal. the phosphatidylinositol-3 kinase inhibitor wortmannin, and the Janus tyrosine kinase, inhibitor AG-490 abolished ET-l-induced contraction. (4) The PKC inhibitor staurosporine but not calphostin C abolished ET-l-induced contraction, and the PTK inhibitor genistein partially reduced ET-l-induced contraction. (5) In arteries precontracted by ET-I, PD-980591 U-0126, wortmannin, AG-490, genistein, and staurosporine produced concentration-dependent relaxation. (6) ET-I induced a biphasic and time-dependent MAPK immunoprecipitation. (7) PD-98059, U-0126, genistein, AG-490, and damnacanthal, but not staurosporine or wortmannin, abolished the effect of ET-I on MAPK immunoreactivity. Conclusions-This study demonstrated that MAPK may be involved in ET-l-induced contraction in rabbit basilar artery. MAPK is downstream of PTK, Src, and Janus tyrosine kinase pathways but may not be downstream of phosphatidylinositol-3 kinase pathways. The possible involvement of PKC in ET-1-induced contraction requires further investigation. Inhibition of these pathways may offer alternative treatment for ET-1-induced contraction and cerebral vasospasm.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据