title: Inhibitors of soluble epoxide hydrolase minimize ischemia-reperfusion-induced cardiac damage in normal, hypertensive, and diabetic rats.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.
authors.forename: Oliul
authors.initials: O
authors.lastname: Islam
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Patil
authors.affiliation: 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.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Goswami
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.
authors.forename: Rema
authors.initials: R
authors.lastname: Razdan
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.|Department of Pharmacology, College of Pharmacy, Jazan University, Jazan, KSA.
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Inamdar
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rizwan
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India.
authors.forename: Jubin
authors.initials: J
authors.lastname: Mathew
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Kin S
authors.initials: KS
authors.lastname: Stephen Lee
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Sung H
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Bruce D
authors.identifier: http://orcid.org/0000-0003-1408-8317
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001565:Benzoates / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D000067268:Isolated Heart Preparation; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; C572961:4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D010880:Piperidines; D004851:Epoxide Hydrolases; C529022:EPHX2 protein, rat
keywords: Endothelial dysfunction; Ischemia/reperfusion-induced myocardial damage; Langendorff's apparatus; Lisinopril; Metformin; sEH inhibitor TPPU and t-TUCB