CALL FOR PAPERS Regulation of Cardiovascular Functions by Eicosanoids and Other Lipid Mediators Effects of selective inhibition of cytochrome P-450 -hydroxylases and ischemic preconditioning in myocardial protection

Nithipatikom, Kasem, Michael P. Endsley, Jeannine M. Moore, Marilyn A. Isbell, John R. Falck, William B. Campbell, and Garrett J. Gross. Effects of selective inhibition of cytochrome P-450 -hydroxylases and ischemic preconditioning in myocardial protection. Am J Physiol Heart Circ Physiol 290: H500–H505, 2006. First published October 7, 2005; doi:10.1152/ajpheart.00918.2005.—Cytochrome P-450 (CYP) -hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP -hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP -hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 1.0% (control), 9.6 1.5% (0.40 mg/kg DDMS), 4.0 2.0% (0.81 mg/kg DDMS), P 0.01]. In addition, 20-hydroxyeicosa-6(Z),15(Z)dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 1.3% (0.032 mg/kg 20-HEDE) and 5.9 1.9% (0.064 mg/kg 20-HEDE), P 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 2.8% (IPC) to 2.5 1.4% (0.81 mg/kg DDMS), P 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP -hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP -hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.