可溶性环氧化物水解酶抑制剂可将正常、高血压和糖尿病大鼠缺血再灌注引起的心脏损伤降至最低。
Inhibitors of soluble epoxide hydrolase minimize ischemia-reperfusion-induced cardiac damage in normal, hypertensive, and diabetic rats.
作者信息
Islam Oliul, Patil Prashanth, Goswami Sumanta K, Razdan Rema, Inamdar Mohammed N, Rizwan Mohammed, Mathew Jubin, Inceoglu Bora, Stephen Lee Kin S, Hwang Sung H, Hammock Bruce D
机构信息
Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.
Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
出版信息
Cardiovasc Ther. 2017 Jun;35(3). doi: 10.1111/1755-5922.12259.
AIM
We designed a study to evaluate the cardioprotective effect of two soluble epoxide hydrolase (sEH) inhibitors, 1-(1-propanoylpiperidin-4-yl)-3-(4-trifluoromethoxy)phenyl)urea (TPPU) and trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB), in ischemia-reperfusion (IR) model.
METHODS
Cardioprotective effects of the sEH inhibitors were evaluated against IR-induced myocardial damage in hearts from normal, hypertensive, and diabetic rats using Langendorff's apparatus. In addition, the effect of sEH inhibitors on endothelial function was evaluated in vitro and ex vivo using isolated rat thoracic aorta.
RESULTS
Ischemia-reperfusion (IR) increased the myocardial damage in hearts from normal rats. IR-induced myocardial damage was augmented in hearts isolated from hypertensive and diabetic rats. Myocardial damage as evident from increase in the activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in heart perfusate was associated with significant decrease in the heart rate and developed tension, and increase in the resting tension in isolated heart. Both sEH inhibitors protected the heart in normal, hypertensive, and diabetic rats subjected to IR injury. The sEH inhibitor t-TUCB relaxed phenylephrine precontracted aorta from normal rats. Relaxant effect of acetylcholine (ACh) was reduced in aortas from diabetic and hypertensive rats compared to normal rats. Pretreatment of sEH inhibitors to diabetic and hypertensive rats increased relaxant effect of ACh on aortas isolated from these rats.
CONCLUSIONS
Prophylactic treatment with sEH inhibitors decreased myocardial damage due to IR, hypertension and diabetes, and decreased endothelial dysfunction created by diabetes and hypertension. Therefore, inhibitors of sEH are useful probes to study cardiovascular pathology, and inhibition of the sEH is a potential approach in the management of IR-induced cardiac damage and endothelial dysfunction-related cardiovascular disorders.
目的
我们设计了一项研究，以评估两种可溶性环氧化物水解酶（sEH）抑制剂，1-(1-丙酰基哌啶-4-基)-3-(4-三氟甲氧基)phenyl)脲（TPPU）和反式-4-{4-[3-(4-三氟甲氧基苯基)-脲基]环己氧基}苯甲酸（t-TUCB）在缺血再灌注（IR）模型中的心脏保护作用。
方法
使用Langendorff装置评估sEH抑制剂对正常、高血压和糖尿病大鼠心脏中IR诱导的心肌损伤的心脏保护作用。此外，使用离体大鼠胸主动脉在体外和离体状态下评估sEH抑制剂对内皮功能的影响。
结果
缺血再灌注（IR）增加了正常大鼠心脏中的心肌损伤。从高血压和糖尿病大鼠分离的心脏中，IR诱导的心肌损伤加剧。心脏灌注液中乳酸脱氢酶（LDH）和肌酸激酶-MB（CK-MB）活性增加所表明的心肌损伤与离体心脏的心率和舒张张力显著降低以及静息张力增加有关。两种sEH抑制剂均保护遭受IR损伤的正常、高血压和糖尿病大鼠的心脏。sEH抑制剂t-TUCB使正常大鼠的苯肾上腺素预收缩主动脉舒张。与正常大鼠相比，糖尿病和高血压大鼠主动脉中乙酰胆碱（ACh）的舒张作用降低。对糖尿病和高血压大鼠预处理sEH抑制剂可增加ACh对从这些大鼠分离的主动脉的舒张作用。
结论
用sEH抑制剂进行预防性治疗可减少因IR、高血压和糖尿病引起的心肌损伤，并减少由糖尿病和高血压引起的内皮功能障碍。因此，sEH抑制剂是研究心血管病理的有用探针，抑制sEH是管理IR诱导的心脏损伤和内皮功能障碍相关心血管疾病的潜在方法。
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