The nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) increases free radical generation and degrades left ventricular function after myocardial ischemia-reperfusion.
BACKGROUND
During reperfusion of ischemic myocardium nitric oxide (NO) reacts with superoxide radicals to form cardiotoxic peroxynitrite, which causes lipid peroxidation. Our hypothesis was that infusion of a NO donor S-nitroso-N-acetylpenicillamine (SNAP) during ischemia-reperfusion would exacerbate the oxidative damage to the myocardium by increased formation of nitrogen radicals.


RESULTS
In 19 open-chest dogs, left anterior descending (LAD) coronary occlusion (15 min)-reperfusion (15 min) sequences were created. Using electron paramagnetic resonance (EPR), we monitored the coronary sinus concentration of ascorbate free radical (Ascz*-), a measure of free radical generation (total oxidative flux). Seven control dogs (Group 1) received intravenous saline infusion during occlusion-reperfusion, while 12 dogs received SNAP infusion (Group 2: 2.5 microg/min per kg SNAP, and Group 3: 5 microg/min per kg SNAP). Left ventricular fractional area shortening was determined by echocardiography. Dogs in Group 3 receiving a high dose of SNAP (5 microg/min per kg) demonstrated a higher Ascz*- concentration increase than the control group. Percent fractional area shortening in Group 1 declined from 77+/-4.0 (baseline) to 54+/-9.0% during ischemia (P<0.05), and then fully recovered to 74+/-3.7% with reperfusion. In the SNAP-treated dogs, the percent fractional area shortening during reperfusion was significantly lower than baseline in Group 2 (55+/-3.9 vs. baseline 74+/-4.4%, P<0.05) and in Group 3 (49+/-5.0 vs. baseline 71+/-4.5%, P<0.01). In five additional dogs, nitrotyrosine immunohistochemistry showed heavy staining of the ischemic-reperfused myocardium.


CONCLUSIONS
The NO donor SNAP increased free radical concentration and exacerbated myocardial oxidative damage after ischemia-reperfusion.
Zhang
Yi
Y
The Cardiovascular Center, Department of Internal Medicine, College of Medicine, University of Iowa Hospital, 200 Hawkins Drive, Iowa City, IA 52242, USA.
Davies
Loyd R
LR
Martin
Sean M
SM
Coddington
William J
WJ
Miller
Francis J
FJ
Buettner
Garry R
GR
Kerber
Richard E
RE
D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005609:Free Radicals / Q000378:metabolism*; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology*; D015425:Myocardial Reperfusion / Q000379:methods*; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000494:pharmacology; D011336:Probability; D012016:Reference Values; D012307:Risk Factors; D026423:S-Nitroso-N-Acetylpenicillamine / Q000009:adverse effects* / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D005609:Free Radicals; D020030:Nitric Oxide Donors; D026423:S-Nitroso-N-Acetylpenicillamine