Epoxyeicosatrienoic acids in cardioprotection: ischemic versus reperfusion injury

• Published in: American journal of physiology. Heart and circulatory physiology 2006-08, Vol.291 (2), p.H537-H542
• Main Authors: Nithipatikom, Kasem, Moore, Jeannine M, Isbell, Marilyn A, Falck, John R, Gross, Garrett J
• Format: Article
• Language: English
• Subjects: 8,11,14-Eicosatrienoic Acid - metabolism; 8,11,14-Eicosatrienoic Acid - pharmacology; Amides - pharmacology; Animals; Arachidonic Acid - metabolism; Cardiotonic Agents; Coronary Circulation - physiology; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dogs; Enzyme Inhibitors - pharmacology; Hemodynamics - physiology; Hydroxyeicosatetraenoic Acids - metabolism; Mixed Function Oxygenases - antagonists & inhibitors; Myocardial Ischemia - physiopathology; Myocardial Ischemia - prevention & control; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - prevention & control; Spectrometry, Mass, Electrospray Ionization; Sulfones - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00071.2006

1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and 2 Departments 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 Address for reprint requests and oth