Peroxynitrite reduces myocardial infarct size and preserves coronary endothelium after ischemia and reperfusion in cats.
BACKGROUND
Peroxynitrite (ONOO-) is purported to exert cytotoxic effects at high doses. However, physiologically relevant concentrations of ONOO- inhibit polymorphonuclear neutrophil (PMN) adhesion to the endothelium and attenuate PMN-mediated contractile dysfunction in isolated perfused rat hearts. We are unaware of any reports in vivo showing effects of peroxynitrite in myocardial ischemia and reperfusion (MI/R). Thus, the purpose of this study was to examine the in vivo effects of a physiologically relevant concentration of ONOO- (1 micromol/L) in a feline model of MI/R injury.


RESULTS
ONOO- (1 micromol/L) or its vehicle (0.9% NaCl at pH 8.4) was infused intraventricularly, starting 10 minutes before reperfusion in cats subjected to 90 minutes of myocardial ischemia and 4.5 hours of reperfusion. ONOO(-)-treated cats demonstrated marked attenuation of cardiac necrosis after MI/R compared with cats receiving only vehicle (P<.001). Moreover, vasorelaxation of ischemic-reperfused left anterior descending (LAD) coronary artery rings in response to the endothelium-dependent dilators acetylcholine and A23187 was greater in rings isolated from ONOO(-)-treated MI/R cats compared with MI/R cats receiving only vehicle, indicating that postreperfusion coronary vascular endothelial function was preserved by ONOO-. ONOO- also significantly reduced adherence of neutrophils to the ischemic-reperfused LAD coronary endothelium. Immunohistochemical localization of P-selectin was also significantly attenuated in hearts from ONOO(-)-infused MI/R cats.


CONCLUSIONS
These data suggest that physiologically relevant concentrations of ONOO- exert significant cardioprotective and vasculoprotective effects in MI/R in cats, at least partially by attenuating PMN-endothelium interactions.
Nossuli
T O
TO
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa 19107, USA.
Hayward
R
R
Scalia
R
R
Lefer
A M
AM
D000818:Animals; D002316:Cardiotonic Agents; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009566:Nitrates / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D019007:P-Selectin / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D013997:Time Factors
D002316:Cardiotonic Agents; D009566:Nitrates; D016877:Oxidants; D019007:P-Selectin; C039642:peroxynitric acid