Effects of selective inhibition of cytochrome P-450 omega-hydroxylases and ischemic preconditioning in myocardial protection.

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.

• Authors: Kasem Nithipatikom, Michael P Endsley, Jeannine M Moore, Marilyn A Isbell, John R Falck, William B Campbell, Garrett J Gross
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 290 Issue 2 Pg. H500-5 (Feb 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16214838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid
• Amides
• Cardiotonic Agents
• Cytochrome P-450 Enzyme Inhibitors
• Hydroxyeicosatetraenoic Acids
• Sulfones
• Arachidonic Acid
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Cytochrome P-450 Enzyme System
• DDMS
• Mixed Function Oxygenases
• cytochrome P-450 omega-hydroxylase

Topics

• Amides (pharmacology)
• Animals
• Arachidonic Acid (metabolism)
• Cardiotonic Agents (pharmacology)
• Coronary Circulation (drug effects)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (metabolism)
• Dogs
• Female
• Hemodynamics (drug effects)
• Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, pharmacology)
• Ischemic Preconditioning, Myocardial
• Male
• Mixed Function Oxygenases (antagonists & inhibitors)
• Myocardial Infarction (pathology)
• Myocardial Ischemia (physiopathology)
• Myocardial Reperfusion Injury (blood, pathology)
• Myocardium (pathology)
• Sulfones (pharmacology)