{"title":"花生四烯酸的细胞色素P450代谢物在糖尿病大鼠缺血再灌注损伤后心功能障碍加重中起作用","authors":"M. H. M. Yousif, I. F. Benter, R. J. Roman","doi":"10.1111/j.1474-8673.2009.00429.x","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p> <b>1</b> This study examined the contribution of cytochrome P450 metabolites of arachidonic acid in mediating ischaemia/reperfusion (I/R)-induced cardiac dysfunction in normal and diabetic rats.</p>\n <p> <b>2</b> We first compared the metabolism of arachidonic acid in microsomes prepared from the hearts of control rats and rats treated with streptozotocin (55 mg kg<sup>−1</sup>) to induce diabetes. The production of dihydroxyeicosatrienoic acids and epoxyeicosatrienoic acids (EETs) were similar in microsomes prepared from the hearts of control and diabetic rats, but the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was two-fold higher in diabetic hearts than in control animals.</p>\n <p> <b>3</b> We then compared the change in left ventricular pressure (<i>P</i><sub>max</sub>), left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance in isolated perfused hearts obtained from control and diabetic animals after 40 min of global ischaemia (I) followed by 30 min of reperfusion (R). The decline in cardiac function was three- to five-fold greater in the hearts obtained from diabetic <i>vs.</i> control animals.</p>\n <p> <b>4</b> Pretreatment of the hearts with <i>N</i>-hydroxy-<i>N</i>′-(4-butyl-2-methyl-phenyl)-formamidine (HET0016, 1 μ<span>m</span>), a selective inhibitor of the synthesis of 20-HETE, for 30 min before I/R resulted in significant improvement in the recovery of cardiac function in the hearts obtained from diabetic but not in control rats. Perfusion with an inhibitor of soluble epoxide hydrolase, 1-cyclohexyl-3-dodecyl urea (CDU), before I/R improved the recovery of cardiac function in hearts obtained from both control and diabetic animals. Perfusion with both HET0016 and CDU resulted in significantly better recovery of cardiac function of diabetic hearts following I/R than that seen using either drug alone. Pretreatment of the hearts with glibenclamide (1 μ<span>m</span>), an inhibitor of ATP-sensitive potassium channels, attenuated the cardioprotective effects of both CDU and HET0016.</p>\n <p> <b>5</b> This is the first study to suggest that acute blockade of the formation of 20-HETE and/or reduced inactivation of EETs could be an important strategy to reduce cardiac dysfunction following I/R events in diabetes.</p>\n </div>","PeriodicalId":100151,"journal":{"name":"Autonomic and Autacoid Pharmacology","volume":"29 1-2","pages":"33-41"},"PeriodicalIF":0.0000,"publicationDate":"2009-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1474-8673.2009.00429.x","citationCount":"52","resultStr":"{\"title\":\"Cytochrome P450 metabolites of arachidonic acid play a role in the enhanced cardiac dysfunction in diabetic rats following ischaemic reperfusion injury\",\"authors\":\"M. H. M. Yousif, I. F. Benter, R. 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The production of dihydroxyeicosatrienoic acids and epoxyeicosatrienoic acids (EETs) were similar in microsomes prepared from the hearts of control and diabetic rats, but the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was two-fold higher in diabetic hearts than in control animals.</p>\\n <p> <b>3</b> We then compared the change in left ventricular pressure (<i>P</i><sub>max</sub>), left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance in isolated perfused hearts obtained from control and diabetic animals after 40 min of global ischaemia (I) followed by 30 min of reperfusion (R). 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引用次数: 52
摘要
本研究探讨了花生四烯酸细胞色素P450代谢物在正常和糖尿病大鼠缺血/再灌注(I/R)诱导的心功能障碍中的作用。我们首先比较了从对照大鼠和用链脲佐菌素(55 mg kg - 1)诱导的大鼠心脏制备的微粒体中花生四烯酸的代谢。二羟基二碳三烯酸和环氧二碳三烯酸(EETs)在糖尿病大鼠心脏制备的微粒体中产生相似，但20-羟基二碳四烯酸(20-HETE)的产生在糖尿病大鼠心脏中是对照组的两倍。然后，我们比较了对照组和糖尿病动物在40分钟全脑缺血(I)和30分钟再灌注(R)后左室压(Pmax)、左室舒张末压、冠状动脉血流和冠状动脉血管阻力的变化。糖尿病动物心脏功能的下降是对照组动物心脏功能下降的三到五倍。4在I/R前，用选择性抑制20-HETE合成的n -羟基- n ' -(4-丁基-2-甲基苯基)-甲脒(HET0016, 1 μm)预处理心脏30分钟，可显著改善糖尿病大鼠心脏功能的恢复，但对照组无此效果。在I/R前灌注可溶性环氧化物水解酶抑制剂1-环己基-3-十二烷基尿素(CDU)，可改善对照组和糖尿病动物心脏功能的恢复。HET0016和CDU灌注后糖尿病心脏I/R术后心功能的恢复明显优于单独使用任何一种药物。用格列本脲(1 μm) (atp敏感钾通道抑制剂)预处理心脏，可以减弱CDU和HET0016的心脏保护作用。这是第一个研究表明，急性阻断20-HETE的形成和/或减少eet的失活可能是减少糖尿病I/R事件后心功能障碍的重要策略。
Cytochrome P450 metabolites of arachidonic acid play a role in the enhanced cardiac dysfunction in diabetic rats following ischaemic reperfusion injury
1 This study examined the contribution of cytochrome P450 metabolites of arachidonic acid in mediating ischaemia/reperfusion (I/R)-induced cardiac dysfunction in normal and diabetic rats.
2 We first compared the metabolism of arachidonic acid in microsomes prepared from the hearts of control rats and rats treated with streptozotocin (55 mg kg−1) to induce diabetes. The production of dihydroxyeicosatrienoic acids and epoxyeicosatrienoic acids (EETs) were similar in microsomes prepared from the hearts of control and diabetic rats, but the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was two-fold higher in diabetic hearts than in control animals.
3 We then compared the change in left ventricular pressure (Pmax), left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance in isolated perfused hearts obtained from control and diabetic animals after 40 min of global ischaemia (I) followed by 30 min of reperfusion (R). The decline in cardiac function was three- to five-fold greater in the hearts obtained from diabetic vs. control animals.
4 Pretreatment of the hearts with N-hydroxy-N′-(4-butyl-2-methyl-phenyl)-formamidine (HET0016, 1 μm), a selective inhibitor of the synthesis of 20-HETE, for 30 min before I/R resulted in significant improvement in the recovery of cardiac function in the hearts obtained from diabetic but not in control rats. Perfusion with an inhibitor of soluble epoxide hydrolase, 1-cyclohexyl-3-dodecyl urea (CDU), before I/R improved the recovery of cardiac function in hearts obtained from both control and diabetic animals. Perfusion with both HET0016 and CDU resulted in significantly better recovery of cardiac function of diabetic hearts following I/R than that seen using either drug alone. Pretreatment of the hearts with glibenclamide (1 μm), an inhibitor of ATP-sensitive potassium channels, attenuated the cardioprotective effects of both CDU and HET0016.
5 This is the first study to suggest that acute blockade of the formation of 20-HETE and/or reduced inactivation of EETs could be an important strategy to reduce cardiac dysfunction following I/R events in diabetes.
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