Title: Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart.

Authors: Gross, Garrett J; Gauthier, Kathryn M; Moore, Jeannine; Falck, John R; Hammock, Bruce D; Campbell, William B; Nithipatikom, Kasem

Published In Am J Physiol Heart Circ Physiol, (2008 Jun)

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.

PubMed ID: 18441205

MeSH Terms: 8,11,14-Eicosatrienoic Acid/analogs & derivatives*; 8,11,14-Eicosatrienoic Acid/metabolism; 8,11,14-Eicosatrienoic Acid/pharmacology*; Adamantane/analogs & derivatives*; Adamantane/pharmacology; Animals; Blood Pressure/drug effects; Cardiovascular Agents/metabolism; Cardiovascular Agents/pharmacology*; Coronary Circulation/drug effects; Diazoxide/pharmacology; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Female; Heart Rate/drug effects; Lauric Acids/pharmacology*; Male; Mitochondria, Heart/drug effects; Mitochondria, Heart/metabolism; Myocardial Infarction/metabolism; Myocardial Infarction/pathology; Myocardial Infarction/physiopathology; Myocardial Infarction/prevention & control*; Myocardium/enzymology; Myocardium/metabolism*; Myocardium/pathology; Potassium Channels/drug effects; Potassium Channels/metabolism