Sulfaphenazole protects heart against ischemia-reperfusion injury and cardiac dysfunction by overexpression of iNOS, leading to enhancement of nitric oxide bioavailability and tissue oxygenation.
The objective of this study was to establish the cardioprotective effect of sulfaphenazole (SPZ), a selective inhibitor of cytochrome P450 2C9 enzyme, in an in vivo rat model of acute myocardial infarction (MI). MI was induced by 30 min ligation of left anterior descending coronary artery, followed by 24 h reperfusion (I/R). The study used 6 groups: I/R (control); SPZ; L-NAME; L-NAME + SPZ; 1400W (an inhibitor of iNOS); 1400W + SPZ. The agents were administered orally through drinking water for 3 days prior to induction of I/R. Myocardial oxygenation (pO(2)) at the I/R site was measured using EPR oximetry. The preischemic pO(2) value was 18 +/- 2 mm Hg in all groups. At 1 h of reperfusion, the SPZ group showed a significantly higher hyperoxygenation when compared to control (45 +/- 1 vs. 34 +/- 2 mm Hg). The SPZ group showed a significant improvement in the contractile functions and reduction in infarct size. Histochemical staining of SPZ-treated hearts exhibited significantly lower levels of superoxide and peroxynitrite, and markedly increased levels of iNOS activity and nitric oxide. Western blot analysis indicated upregulation of Akt and attenuation of p38MAPK activities in the reperfused myocardium. The study established that SPZ attenuated myocardial I/R injury through overexpression of iNOS, leading to enhancement of nitric oxide bioavailability and tissue oxygenation.
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Mahmood
M
Khan
Iyyapu K
IK
Mohan
Vijay K
VK
Kutala
Sainath R
SR
Kotha
Narasimham L
NL
Parinandi
Robert L
RL
Hamlin
Periannan
P
Kuppusamy
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D006339:Heart Rate; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D013426:Sulfaphenazole / Q000494:pharmacology*
D002316:Cardiotonic Agents; D013426:Sulfaphenazole; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011494:Protein Kinases; D010100:Oxygen