Peroxynitrite (ONOO$\sp-),$ an intermediate formed from the equimolar interaction of nitric oxide (NO) and superoxide, is thought to be an important mediator of tissue injury in myocardial ischemia-reperfusion, as well as other inflammatory disease states. However, physiologically relevant (i.e., maximally achievable) concentrations of ONOO$\sp-$ significantly decreased neutrophil-endothelium interactions in the rat mesentery in recent studies. Therefore, the concentration-response relationship of infusion of different concentrations of ONOO$\sp-$ in a feline model of myocardial ischemia-reperfusion was examined in an effort to provide data on the mechanisms responsible for the observed effects of ONOO$\sp-$ infusion. Cats subjected to 90 min of ischemia (I) followed by 270 min of reperfusion (R) were infused with different concentrations of ONOO$\sp-$ 10 min before R, and continuing throughout R. We observed that infusion of 2 ONOO$\sp-$ provided significant cardioprotection, whereas either 0.2 $\mu$M or 20 $\mu$M ONOO$\sp-$ did not protect. ONOO$\sp-$ at 2 $\mu$M also preserved coronary endothelial function, decreased P-selectin expression, and attenuated polymorphonuclear leukocyte (PMN) adherence to the vascular endothelium. ONOO$\sp-$ did not exert its cardioprotective effects by acting as a direct NO donor in solution, or by inhibiting platelet aggregation. However, in vitro, ONOO$\sp-$ reacted with glutathione to form S-nitrosoglutathione, which can act as a NO carrier and exert beneficial effects, such as stimulation of soluble guanylyl cyclase. Thus, the data presented in this thesis indicate that maximally achievable concentrations of ONOO$\sp-$ exert significant cardioprotective effects, in part by forming S-nitrosothiols which could decrease cell surface expression of P-selectin leading to reduced PMN-endothelium interactions.
