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-hydroxylases and Ischemic Preconditioning in Myocardial Protection
1 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
2 Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
* To whom correspondence should be addressed. E-mail: ggross{at}mcw.edu.
Cytochrome P450 (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 (IS, expressed as a percent 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 as 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 to 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 ischemic preconditioning (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.
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