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


CONCLUSIONS
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.
Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA. james-martins@uiowa.edu.
James B
JB
Martins
Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA. ashok-chaudhary@uiowa.edu.
Ashok K
AK
Chaudhary
Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA. shuxia-jiang@uiowa.edu.
Shuxia
S
Jiang
Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA. michael-kwofie@uiowa.edu.
Michael
M
Kwofie
Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA. prescott-mackie@uiowa.edu.
Prescott
P
Mackie
Division of Cardiovascular Diseases, Departments of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, IA, USA. francis-miller@uiowa.edu.
Francis J
FJ
Miller
D000098:Acetophenones / Q000494:pharmacology / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D008297:Male; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010117:Oxypurinol / Q000494:pharmacology / Q000627:therapeutic use; D017180:Tachycardia, Ventricular / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D014463:Ultrasonography; D014693:Ventricular Fibrillation / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000098:Acetophenones; C056165:acetovanillone; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D010117:Oxypurinol