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Int. J. Mol. Sci. 2014, 15(11), 20079-20100; doi:10.3390/ijms151120079

Role of NADPH Oxidase and Xanthine Oxidase in Mediating Inducible VT/VF and Triggered Activity in a Canine Model of Myocardial Ischemia

Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA
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Received: 23 August 2014 / Revised: 17 October 2014 / Accepted: 21 October 2014 / Published: 4 November 2014
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)
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Abstract

Background: Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations (DADs) is reproducibly inducible after anterior coronary artery occlusion. Both VT/VF and TA can be blocked by reducing reactive oxygen species (ROS). We tested the hypothesis that inhibition of NADPH oxidase and xanthine oxidase would block VT/VF. Methods: 69 dogs received apocynin (APO), 4 mg/kg intraveneously (IV), oxypurinol (OXY), 4 mg/kg IV, or both APO and OXY (BOTH) agents, or saline 3 h after coronary occlusion. Endocardium from ischemic sites (3-D mapping) was sampled for Rac1 (GTP-binding protein in membrane NADPH oxidase) activation or standard microelectrode techniques. Results (mean ± SE, * p < 0.05): VT/VF originating from ischemic zones was blocked by APO in 6/10 *, OXY in 4/9 *, BOTH in 5/8 * or saline in 1/27; 11/16 VT/VFs blocked were focal. In isolated myocardium, TA was blocked by APO (10−6 M) or OXY (10−8 M). Rac1 levels in ischemic endocardium were decreased by APO or OXY. Conclusion: APO and OXY suppressed focal VT/VF due to DADs, but the combination of the drugs was not more effective than either alone. Both drugs inhibited ischemic Rac1 with inhibition by OXY suggesting ROS-induced ROS. The inability to totally prevent VT/VF suggests that other mechanisms also contribute to ischemic VT. View Full-Text
Keywords: ventricular tachycardia/fibrillation; triggered activity; myocardial ischemia; NADPH oxidase ventricular tachycardia/fibrillation; triggered activity; myocardial ischemia; NADPH oxidase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Martins, J.B.; Chaudhary, A.K.; Jiang, S.; Kwofie, M.; Mackie, P.; Miller, F.J. Role of NADPH Oxidase and Xanthine Oxidase in Mediating Inducible VT/VF and Triggered Activity in a Canine Model of Myocardial Ischemia. Int. J. Mol. Sci. 2014, 15, 20079-20100.

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