Role of NADPH oxidase and xanthine oxidase in mediating inducible VT/VF and triggered activity in a canine model of myocardial ischemia

James B Martins; Ashok K Chaudhary; Shuxia Jiang; Michael Kwofie; Prescott Mackie; Francis J Miller

doi:10.3390/ijms151120079

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Role of NADPH oxidase and xanthine oxidase in mediating inducible VT/VF and triggered activity in a canine model of myocardial ischemia

Journal article

Open access

Peer reviewed

Role of NADPH oxidase and xanthine oxidase in mediating inducible VT/VF and triggered activity in a canine model of myocardial ischemia

James B Martins, Ashok K Chaudhary, Shuxia Jiang, Michael Kwofie, Prescott Mackie and Francis J Miller

International journal of molecular sciences, Vol.15(11), pp.20079-20100

11/04/2014

DOI: 10.3390/ijms151120079

PMCID: PMC4264157

PMID: 25375191

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Abstract

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. 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. 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.

Acetophenones - pharmacology

Acetophenones - therapeutic use

Action Potentials - drug effects

Animals

Blotting, Western

Disease Models, Animal

Dogs

Female

Male

Myocardial Ischemia - diagnostic imaging

Myocardial Ischemia - drug therapy

Myocardial Ischemia - enzymology

Myocardial Ischemia - physiopathology

NADPH Oxidases - antagonists & inhibitors

NADPH Oxidases - metabolism

Oxypurinol - pharmacology

Oxypurinol - therapeutic use

rac1 GTP-Binding Protein - metabolism

Tachycardia, Ventricular - complications

Tachycardia, Ventricular - drug therapy

Tachycardia, Ventricular - enzymology

Tachycardia, Ventricular - physiopathology

Ultrasonography

Ventricular Fibrillation - complications

Ventricular Fibrillation - drug therapy

Ventricular Fibrillation - enzymology

Ventricular Fibrillation - physiopathology

Xanthine Oxidase - antagonists & inhibitors

Xanthine Oxidase - metabolism

Details

Title: Subtitle: Role of NADPH oxidase and xanthine oxidase in mediating inducible VT/VF and triggered activity in a canine model of myocardial ischemia
Creators: James B Martins - University of Iowa
Ashok K Chaudhary - University of Iowa
Shuxia Jiang - University of Iowa
Michael Kwofie - University of Iowa
Prescott Mackie - University of Iowa
Francis J Miller - University of Iowa
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.15(11), pp.20079-20100
DOI: 10.3390/ijms151120079
PMID: 25375191
PMCID: PMC4264157
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Grant note: I01 BX001729 / BLRD VA
Language: English
Date published: 11/04/2014
Academic Unit: Radiology; Internal Medicine
Record Identifier: 9984318685002771

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6 Times Cited - Web of Science