Cytochrome P450 ω-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal KATP channel
Cytochrome P450 ω-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal KATP channel
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DOI：
10.1016/j.yjmcc.2004.10.008
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发表时间：
2004-12-01
影响因子：
5
通讯作者：
Gross, GJ
中科院分区：
文献类型：
--
作者：
Gross, ER;Nithipatikom, K;Gross, GJ
20-羟基二十碳三烯酸(20-HETE)被细胞色素P450(CYP)omega-羟基酶的药理抑制剂预先抑制，在缺血前给药可缩小犬的梗塞范围。然而，目前尚不清楚这些药物在再灌流前给药是否能缩小心肌梗死范围，以及肌膜和/或线粒体K-ATP通道(SK(ATP)和MK(ATP))是否有助于心肌保护。因此，我们确定了环氧合酶和omega-羟基酶的特异性CYP抑制剂在缺血前或再灌流前给予是否具有心脏保护作用，此外，HMR-1098选择性抑制SK(ATP)或5-羟基癸酸(5-HD)选择性抑制MK(ATP)是否可以消除这一作用。雄性SD大鼠缺血30min，再灌流2小时。模型组给予咪康唑(MIC3 mg/kg)、17-十八烷酸(17-ODYA)、N-甲磺酰基-12，12-二溴-11-烯胺(N-甲磺酰基-12，12-二溴-11-烯胺，0、4或4 mg/kg)、N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide(MS-PPOH，环氧合酶抑制剂3 mg/kg)或赋形剂。大鼠在再灌流前10分钟给予HMR-1098(6 mg/kg)或5-HD(10 mg/kg)，大鼠各亚组在再灌流前5分钟也给予MIC或17-ODYA。DDMS和17-ODYA呈剂量依赖性地缩小心肌梗死面积。与赋形剂相比，用MIC17-ODYA和DDMS治疗的大鼠，而不是MS-PPOH治疗的大鼠，在缺血或再灌流前给药时，心肌梗死面积有类似的缩小。HMR-1098也可阻断MIC和17-ODYA所致的心肌梗死面积缩小，但不能阻断5-HD。这些数据提示了一种新的心脏保护途径，包括在再灌流过程中抑制CYP omega-羟基酶和随后激活SK(ATP)通道。(C)2004爱思唯尔有限公司。保留所有权利。
Inhibition of 20-hydroxyeicosatrienoic acid (20-HETE), by pretreatment with pharmacological inhibitors of cytochrome P450 (CYP) omega-hydroxylase, has been shown to reduce infarct size in canines when administered prior to ischemia. However, it is unknown whether these agents reduce infarct size when administered just prior to reperfusion and if the sarcolemmal and/or mitochondrial K-ATP channels (sK(ATP) and mK(ATP)) contribute to cardioprotection. Therefore, we determined whether specific CYP inhibitors for epoxygenases and omega-hydroxylases are cardioprotective when given either prior to ischemia or prior to reperfusion and furthermore, if selective inhibition of the sK(ATP) by HMR-1098 or mK(ATP) by 5-hydroxydecanoic acid (5-HD) could abrogate this effect. Male Sprague-Dawley rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. Groups received either miconazole (MIC, non-selective CYP inhibitor, 3 mg/kg), 17-octadecynoic acid (17-ODYA, CYP omega-hydroxylase inhibitor, 0,3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS, CYP omega-hydroxylase inhibitor, 0,4 or 4 mg/kg), N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH, CYP epoxygenase inhibitor, 3 mg/kg), or vehicle either 10 minutes prior to ischemia or 5 minutes prior to reperfusion. Rats also received either HMR-1098 (6 mg/kg) or 5-HD (10 mg/kg) 10 minutes prior to reperfusion, with subsets of rats also receiving either MIC or 17-ODYA 5 minutes prior to reperfusion. DDMS and 17-ODYA dose dependently reduced infarct size. Rats treated with MIC 17-ODYA and DDMS, but not MS-PPOH, produced comparable reductions in infarct size when administered prior to ischemia or reperfusion compared to vehicle. HMR-1098, but not 5-HD, also blocked the infarct size reduction afforded by MIC and 17-ODYA. These data suggest a novel cardioprotective pathway involving CYP omega-hydroxylase inhibition and subsequent activation of the sK(ATP) channel during reperfusion. (C) 2004 Elsevier Ltd. All rights reserved.