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Epoxyeicosatrienoic acids in cardioprotection: ischemic versus reperfusion injury

¹Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and ²Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 17 January 2006 ; accepted in final form 8 February 2006

Cytochrome P-450 (CYP) epoxygenases and their arachidonic acid (AA) metabolites, the epoxyeicosatrienoic acids (EETs), have been shown to produce increases in postischemic function via ATP-sensitive potassium channels (K_ATP); however, the direct effects of EETs on infarct size (IS) have not been investigated. We demonstrate that two major regioisomers of CYP epoxygenases, 11,12-EET and 14,15-EET, significantly reduced IS in dogs compared to control (22.1 ± 1.8%), whether administered 15 min before 60 min of coronary occlusion (6.4 ± 1.9%, 11,12-EET; and 8.4 ± 2.4%, 14.15-EET) or 5 min before 3 h of reperfusion (8.8 ± 2.1%, 11,12-EET; and 9.7 ± 1.4%, 14,15-EET). Pretreatment with the epoxide hydrolase metabolite of 14,15-EET, 14,15-dihydroxyeicosatrienoic acid, had no effect. The protective effect of 11,12-EET was abolished (24.3 ± 4.6%) by the K_ATP channel antagonist glibenclamide. Furthermore, one 5-min period of ischemic preconditioning (IPC) reduced IS to a similar extent (8.7 ± 2.8%) to that observed with the EETs. The selective CYP epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), did not block the effect of IPC. However, administration of MS-PPOH concomitantly with N-methylsulfonyl-12,12-dibromododec-11-enanide (DDMS), a selective inhibitor of endogenous CYP -hydroxylases, abolished the reduction in myocardial IS expressed as a percentage of area at risk (IS/AAR) produced by DDMS (4.6 ± 1.2%, DDMS; and 22.2 ± 3.4%, MS-PPOH + DDMS). These data suggest that 11,12-EET and 14,15-EET produce reductions in IS/AAR primarily at reperfusion. Conversely, inhibition of CYP epoxygenases and endogenous EET formation by MS-PPOH, in the presence of the CYP -hydroxylase inhibitor DDMS blocked cardioprotection, which suggests that endogenous EETs are important for the beneficial effects observed when CYP -hydroxylases are inhibited. Finally, the protective effects of EETs are mediated by cardiac K_ATP channels.

cytochrome P-450 epoxygenase; 11,12-epoxyeicosatrienoic acid; 14,15-epoxyeicosatrienoic acid; 20-hydroxyeicosatetraenoic acid; ischemic preconditioning; adenosine 5'-triphosphate-sensitive potassium channels

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