title: Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA. ggross@mcw.edu
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Gauthier
authors.forename: Jeannine
authors.initials: J
authors.lastname: Moore
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000378:metabolism / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007850:Lauric Acids / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; C494022:14,15-eicosa-5-enoic acid; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D003981:Diazoxide; D000218:Adamantane