tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK.
tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK.
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DOI：
10.1016/j.brainres.2010.12.052
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发表时间：
2011-02-28
期刊：
影响因子：
2.9
通讯作者：
Higazi AA
中科院分区：
文献类型：
--
作者：
Armstead WM;Riley J;Cines DB;Higazi AA
FDA唯一批准的急性中风治疗是组织型纤溶酶原激活剂（tPA）。然而，tPA增强损伤软膜动脉扩张反应低血压后缺氧/缺血（H/I）的猪。ATP和Ca敏感性钾通道（Katp和Kca）是脑血管紧张性的重要调节者，介导低血压时的血管舒张反应。有丝分裂原活化蛋白激酶（MAPK）是至少3种激酶（ERK、p38和JNK）的家族，在H/I后上调，其中ERK同种型促进血管扩张损伤。本研究探讨了H/I对Katp和Kca诱导的软脑膜动脉扩张的影响以及tPA和ERK在配备有闭合颅窗的仔猪损伤期间/之后的作用。H/I减弱了由Katp激动剂克罗卡林、降钙素基因相关肽（CGRP）和Kca激动剂NS 1619诱导的血管舒张; tPA加剧了每种作用。损伤前或损伤后用EEIIMD（一种来自纤溶酶原激活剂-1的六肽）和ERK拮抗剂U 0126治疗可预防Katp和Kca通道激动剂诱导的血管舒张功能障碍，而非活性类似物EEIIMR则无作用。H/I后ERK表达上调，tPA可增强ERK表达。这些数据表明H/I损害K通道介导的血管舒张。tPA通过上调ERK增强损伤后K通道功能的丧失。这些数据表明，用于治疗CNS缺血性疾病的溶栓治疗可通过损害阳离子介导的脑血管张力控制来失调脑血流动力学。
The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, tPA potentiates impairment of pial artery dilation in response to hypotension after hypoxia/ischemia (H/I) in pigs. ATP and Ca sensitive K channels (Katp and Kca) are important regulators of cerebrovascular tone and mediate cerebrovasodilation in response to hypotension. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is upregulated after H/I, with the ERK isoform contributing to vasodilator impairment. This study examined the effect of H/I on Katp and Kca induced pial artery dilation and the roles of tPA and ERK during/after injury in piglets equipped with a closed cranial window. H/I blunted vasodilation induced by the Katp agonists cromakalim, calcitonin gene related peptide (CGRP) and the Kca agonist NS 1619; the effect of each was exacerbated by tPA. Pre- or post-injury treatment with EEIIMD, a hexapeptide derived from plasminogen activator-1, and ERK antagonist U 0126 prevented Katp and Kca channel agonist induced vasodilator impairment while the inactive analogue EEIIMR had no effect. ERK was upregulated after H/I, which was potentiated by tPA. These data indicate that H/I impairs K channel mediated cerebrovasodilation. tPA augments loss of K channel function after injury by upregulating ERK. These data suggest that thrombolytic therapy for treatment of CNS ischemic disorders can dysregulate cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone.
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UPA通过LRP和ERK MAPK损害缺氧/缺血后的脑炎。
影响因子：
2.9
作者：
Armstead, William M.;Cines, Douglas B.;Bdeir, Khalil;Kulikovskaya, Irina;Stein, Sherman C.;Higazi, Abd Al-Roof
通讯作者：
Higazi, Abd Al-Roof
影响因子：
8.3
作者：
Armstead, WM
通讯作者：
Armstead, WM
影响因子：
8
作者：
Lynch, JK;Hirtz, DG;Nelson, KB
通讯作者：
Nelson, KB
DOI：
10.1073/pnas.96.22.12866
发表时间：
1999-10-26
影响因子：
11.1
作者：
Alessandrini, A;Namura, S;Bonventre, JV
通讯作者：
Bonventre, JV
DOI：
10.1073/pnas.89.16.7427
发表时间：
1992-08-15
影响因子：
11.1
作者：
BU, GJ;WILLIAMS, S;SCHWARTZ, AL
通讯作者：
SCHWARTZ, AL