Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart
Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart
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DOI：
10.1152/ajpheart.00186.2008
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Nithipatikom, Kasem
中科院分区：
文献类型：
--
作者：
Gross, Garrett J.;Gauthier, Kathryn M.;Nithipatikom, Kasem
先前，我们证明（17）11,12和14,15-环氧二碳三烯酸（EETs）可以显著减少心肌梗死面积。虽然假设EET的这种心脏保护作用是由于与膜结合受体的特定相互作用，但没有证据表明新型EET拮抗剂选择性地阻断狗的EET作用。我们的目的是研究11,12和14,15-EET，可溶性环氧化物水解酶抑制剂，12 -(3-adamantan-1-yl-ureido)-十二烷酸（AUDA），以及假设的选择性EET拮抗剂，14,15-环氧-5(Z)-烯酸（14,15- eze），对巴比妥麻醉的狗在冠状动脉闭塞60分钟和再灌注3小时后梗死面积的影响。此外，我们还研究了14,15- eeze对选择性线粒体atp敏感钾通道开启剂二氮氧化物的心脏保护作用。11,12和14,15- eet均能显著降低梗死面积[以危险面积百分比（IS/AAR）表示]，分别从21.8 +/- 1.6%（对照组）降至8.7 +/- 2.2%和9.4 +/- 1.3%。同样，AUDA显著降低IS/AAR，分别从21.8 +/- 1.6降低至14.4 +/- 1.2%（低剂量）和9.4 +/- 1.8%（高剂量）。有趣的是，低剂量AUDA联合14,15- eet使IS/AAR降至5.8 +/- 1.6% (P < 0.05)，比单独使用任何一种药物都要明显。二氮氧化合物也显著降低IS/AAR（10.2 +/- 1.9%）。相比之下，14,15- eeze对IS/AAR没有影响（21.0 +/- 3.6%），但完全消除了11,12- eet（17.8 +/- 1.4%）、14,15- eet（19.2 +/- 2.4%）和AUDA（19.3 +/- 1.6%）的影响，但没有二氮氧化合物（10.4 +/- 1.4%）的影响。这些结果表明，通过外源性EET或间接阻断EET代谢，激活EET通路，作用于一个假定的受体，产生显著的心脏保护作用，这两种方法的结合产生了协同效应。这些数据还表明，14,15- eeze并没有阻断线粒体atp敏感的钾通道，作为拮抗eet的心脏保护作用的机制。
Previously, we demonstrated (17) that 11,12 -and 14,15-epoxyeicosatrienoic acids (EETs) produce marked reductions in myocardial infarct size. Although it is assumed that this cardioprotective effect of the EETs is due to a specific interaction with a membrane-bound receptor, no evidence has indicated that novel EET antagonists selectively block the EET actions in dogs. Our goals were to investigate the effects of 11,12 -and 14,15-EET, the soluble epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), and the putative selective EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), on infarct size of barbital anesthetized dogs subjected to 60 min of coronary artery occlusion and 3 h of reperfusion. Furthermore, the effect of 14,15-EEZE on the cardioprotective actions of the selective mitochondrial ATP-sensitive potassium channel opener diazoxide was investigated. Both 11,12 -and 14,15-EET markedly reduced infarct size [expressed as a percentage of the area at risk (IS/AAR)] from 21.8 +/- 1.6% (vehicle) to 8.7 +/- 2.2 and 9.4 +/- 1.3%, respectively. Similarly, AUDA significantly reduced IS/AAR from 21.8 +/- 1.6 to 14.4 +/- 1.2% (low dose) and 9.4 +/- 1.8% (high dose), respectively. Interestingly, the combination of the low dose of AUDA with 14,15-EET reduced IS/AAR to 5.8 +/- 1.6% (P < 0.05), further than either drug alone. Diazoxide also reduced IS/AAR significantly (10.2 +/- 1.9%). In contrast, 14,15-EEZE had no effect on IS/AAR by itself (21.0 +/- 3.6%), but completely abolished the effect of 11,12-EET (17.8 +/- 1.4%) and 14,15-EET (19.2 +/- 2.4%) and AUDA (19.3 +/- 1.6%), but not that of diazoxide (10.4 +/- 1.4%). These results suggest that activation of the EET pathway, acting on a putative receptor, by exogenous EETs or indirectly by blocking EET metabolism, produced marked cardioprotection, and the combination of these two approaches resulted in a synergistic effect. These data also suggest that 14,15-EEZE is not blocking the mitochondrial ATP-sensitive potassium channel as a mechanism for antagonizing the cardioprotective effects of the EETs.