Peroxynitrite in Cardiac Ischemia/Reperfusion Injury

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Nitro-compounds (e.g., nitroglycerin), as exogenous NO donors, have been used to treat MI for over one hundred years. The benefits of NO- treatment in reperfusion, however, have recently been challenged. Biochemical evidence reveals that ONOO-, the reaction product of NO with O2, is a highly reactive moiety that causes tissue damage comparable to that caused by OH Although these in vitra studies support a role for ONOO- in myocardial reperfusion injury, extension of these observations to relevant whole organs or to in viva models is lacking. More importantly, recent studies suggest that the effects of ONOO- are critically dependent on the microenvironment in which this oxidant is produced. The long-term goal of this project is to enhance the understanding of ONOO- in reperfusion injury. In specific aim number 1, chemically-synthesized ONOO- will be continually infused into the left atrium of rabbits at various doses and intervals during coronary occlusion or reperfusion. The effects of this exogenous ONOO- on infarct size, cardiac function, and PMN accumulation will be evaluated in a clinically relevant in vivo model. In specific aim number 2, endogenous ONOO- will be inhibited by administration of superoxide, nitric oxide, or ONOO- scavenger. The role of endogenously formed ONOO- in reperfusion will be evaluated and different strategies aimed at decreasing ONOO- concentration to a level that protects against reperfusion injury will be studied- In specific aim number3, the mechanisms by which ONOO- influences PMN-EC interactions will be determined in isolated rabbit neutrophils and cultured rabbit microvascular endothelial cells. The proposed studies are clinically relevant because the results may alter future treatment of cardiac ischemia. The studies outlined in this proposal are fundamental to understanding the role of NO in ischemia-reperfusion injury, and are prerequisite to clinical trials designed to decrease reperfusion injury through the manipulation of NO production.