Faculty Collaboration Database

Effects of selective inhibition of cytochrome P-450 omega-hydroxylases and ischemic preconditioning in myocardial protection. Am J Physiol Heart Circ Physiol 2006 Feb;290(2):H500-5

Date

10/11/2005

Pubmed ID

16214838

DOI

10.1152/ajpheart.00918.2005

Scopus ID

2-s2.0-33644859072 (requires institutional sign-in at Scopus site)   40 Citations

Abstract

Cytochrome P-450 (CYP) omega-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 omega-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 omega-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 omega-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 omega-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.

Author List

Nithipatikom K, Endsley MP, Moore JM, Isbell MA, Falck JR, Campbell WB, Gross GJ

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amides
Animals
Arachidonic Acid
Cardiotonic Agents
Coronary Circulation
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Dogs
Female
Hemodynamics
Hydroxyeicosatetraenoic Acids
Ischemic Preconditioning, Myocardial
Male
Mixed Function Oxygenases
Myocardial Infarction
Myocardial Ischemia
Myocardial Reperfusion Injury
Myocardium
Sulfones