Potassium channel dysfunction in cerebral arteries of insulin-resistant rats is mediated by reactive oxygen species
Potassium channel dysfunction in cerebral arteries of insulin-resistant rats is mediated by reactive oxygen species
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DOI：
10.1161/01.str.0000119753.05670.f1
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发表时间：
2004-04-01
期刊：
影响因子：
8.3
通讯作者：
Busija, DW
中科院分区：
文献类型：
--
作者：
Erdös, B;Simandle, SA;Busija, DW
背景和目的--胰岛素抵抗(IR)增加了人类中风的风险。一个可能的潜在因素是K+通道功能改变导致的脑血管功能障碍。因此，本研究的目的是研究K+通道介导的IR脑动脉的舒张性。方法对果糖喂养的IR大鼠和对照大鼠的大脑中动脉(MCA)进行加压实验。结果：在10(-6)mol/L时，IR大鼠对BKCa通道介导的伊洛前列素的扩张性反应比对照动脉降低(19+/-2%比33+/-2%)。同样，IR MCAS组对K-ATP开放剂吡那地尔的松弛作用(17+/-2%)低于对照组(10(-5)mol/L时的38+/-2%)。IR也可减少降钙素基因相关肽引起的血管扩张中依赖于K-ATP通道的成分；然而，由于非特定K+通道介导的代偿机制，IR的松弛幅度保持不变。相反，对照动脉和IR动脉由细胞外[K+]升高(4~12 mm ol/L)引起的K-ir通道介导的松弛作用相似。分别用Ba2+和4-氨基吡啶阻断K-ir和K-v通道可使两个实验组的大脑中动脉收缩，但差异无统计学意义。超氧化物歧化酶(200U/m L)加过氧化氢酶(150U/m L)可恢复伊洛前列素和吡那地尔对IR动脉的舒缩作用。免疫印迹结果显示，IR对K+通道成孔亚基的表达无明显影响。结论IR诱导了一种由活性氧介导的类型特异性K+通道功能障碍。K-ATP和BKCa通道依赖性血管反应的改变可能是IR发生脑血管事件风险增加的原因之一。
Background and Purpose-Insulin resistance (IR) increases the risk of stroke in humans. One possible underlying factor is cerebrovascular dysfunction resulting from altered K+ channel function. Thus, the goal of this study was to examine K+ channel-mediated relaxation in IR cerebral arteries.Methods-Experiments were performed on pressurized isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats.Results-Dilator responses to iloprost, which are BKCa channel mediated, were reduced in the IR compared with control arteries (19+/-2% versus 33+/-2% at 10(-6) mol/L). Similarly, relaxation to the K-ATP opener pinacidil was diminished in the IR MCAs (17+/-2%) compared with controls (38+/-2% at 10(-5) mol/L). IR also reduced the K-ATP channel-dependent component in calcitonin gene-related peptide-induced dilation; however, the magnitude of the relaxation remained unchanged in IR because of a nonspecified K+ channel-mediated compensatory mechanism. In contrast, K-ir channel-mediated relaxation elicited by increases in extracellular [K+] (4 to 12 mmol/L) was similar in the control and IR arteries. Blockade of the K-ir and K-v channels with Ba2+ and 4-aminopyridine, respectively, constricted the MCAs in both experimental groups with no significant difference. Pretreatment of arteries with superoxide dismutase (200 U/mL) plus catalase (150 U/mL) restored the dilatory responses to iloprost and pinacidil in the IR arteries. Immunoblots showed that the expressions of the pore-forming subunits of the examined K+ channels are not altered by IR.Conclusions-IR induces a type-specific K+ channel dysfunction mediated by reactive oxygen species. The alteration of K-ATP and BKCa channel-dependent vascular responses may be responsible for the increased risk of cerebrovascular events in IR.