Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice.
Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice.
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DOI：
10.1152/ajpheart.00431.2004
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发表时间：
2004-11
期刊：
影响因子：
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通讯作者：
Xiaoying Wang;Chang Yin;Lei Xi;R. Kukreja
中科院分区：
文献类型：
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作者：
Xiaoying Wang;Chang Yin;Lei Xi;R. Kukreja
开放钙激活的K+(KCA)通道已被证明可以提供早期的心脏保护。目前尚不清楚这些通道的开放是否也会导致延迟的心脏保护。此外，我们还确定了一氧化氮合酶(NOSS)的参与，一氧化氮合酶(NOSS)参与了线粒体ATP敏感K+(KATP)通道的开放而引起的心肌保护。成年雄性ICR小鼠在全脑缺血30min和再灌流(I/R)60min前10min或24 h分别给予KCA通道开放剂NS-1619。缺血再灌流前给予NS-1619(10微米)10分钟，与赋形剂(DMSO)治疗组相比，脑梗塞面积缩小(P<；0.05)。NS-1619的这种梗塞限制作用与改善I/R后的心功能恢复有关。与KCA通道阻滞剂帕西林(1微米)共同给予NS-1619可取消NS-1619的保护作用。同样，预先给予NS-1619(1 mg/kg ip)可引起24 h后的延迟保护(P<；0.05)。有趣的是，一氧化氮合酶抑制剂诺米伽-硝基-L-精氨酸甲酯(15 mg/kg ip)不能阻断NS-1619诱导的晚期保护作用。与二氮嗪(线粒体KATP通道的开放剂)不同，NS-1619不增加诱导型或内皮型一氧化氮合酶的表达。Western印迹分析表明，小鼠心脏组织中存在KCA通道的α和β亚基。我们得出结论，KCA通道的开放通过一种独立于一氧化氮的机制导致早期和延迟的预适应效应。
Opening of Ca2+-activated K+ (KCa) channels has been shown to confer early cardioprotection. It is unknown whether the opening of these channels also induces delayed cardioprotection. In addition, we determined the involvement of nitric oxide synthases (NOSs), which have been implicated in cardioprotection induced by opening of mitochondrial ATP-sensitive K+ (KATP) channels. Adult male ICR mice were pretreated with the KCa-channel opener NS-1619 either 10 min or 24 h before 30 min of global ischemia and 60 min of reperfusion (I/R) in Langendorff mode. Infusion of NS-1619 (10 microM) for 10 min before I/R led to smaller infarct sizes as compared with the vehicle (DMSO)-treated group (P <0.05). This infarct-limiting effect of NS-1619 was associated with improvement in ventricular functional recovery after I/R. The NS-1619-induced protection was abolished by coadministration with the KCa-channel blocker paxilline (1 microM). Similarly, pretreatment with NS-1619 (1 mg/kg ip) induced delayed protection 24 h later (P <0.05). Interestingly, the NS-1619-induced late protection was not blocked by the NOS inhibitor Nomega-nitro-L-arginine methyl ester (15 mg/kg ip). Unlike diazoxide (the opener of mitochondrial KATP channels), NS-1619 did not increase the expression of inducible or endothelial NOS. Western blot analysis demonstrated the existence of alpha- and beta-subunits of KCa channels in mouse heart tissue. We conclude that opening of KCa channels leads to both early and delayed preconditioning effects through a mechanism that is independent of nitric oxide.