AGE, REACTIVE OXYGEN METABOLITES AND MYOCARDIAL INJURY

本研究的总体目标是确定活性氧的作用

The overall goal of this study is to define the role of reactive oxygen metabolites in myocardial cell injury in immature and mature hearts. We have shown that the isolated immature rabbit heart is more tolerant to a cycle of ischemia and reperfusion than the mature heart. The basis for this tolerance is unknown. Myocardial cell injury induced by a cycle of ischemia and reperfusion is known to be caused in part by the generation of reactive oxygen metabolites. We have shown that Electron Spin Resonance (ESR) spectroscopy can detect free radical generation in isolated perfused rat and rabbit hearts. The aim of this study is to test the hypothesis that myocardial maturation entails an alteration in the myocardial response to reactive oxygen metabolites manifested during a cycle of ischemia and reperfusion. We will determine the age of transition for altered response to ischemia/reperfusion as assessed by functional criteria. We will then assess the species and extent of free radicals and paramagnetic metabolites present in myocardium during the cycle of aerobic perfusion/ischemia/reperfusion in pre-transition, transition and post-transition ages, and then (Specific Aim 3) assess the defense mechanisms against reactive oxygen metabolites during the aerobic perfusion/ischemia/reperfusion cycle in the three age groups. Finally we will assess the direct impact that free radicals and an oxidant will have on aerobic function in vivo by perfusing the coronary system of the isolated heart with these agents. This hypothesis will be tested in one species, the rabbit. The isolated working heart preparation will be used to facilitate discrete well-controlled observations of generation of toxic radical species and of defense mechanisms against reactive oxygen metabolites as these relate to the maturational process. ESR spectroscopy has recently been used by us to detect directly radical species in isolated hearts and will be used to provide direct evidence for free radical and paramagnetic metabolite generation during ischemia and reperfusion is less in immature than mature hearts, that the immature heart is more tolerant to free radicals and oxidant generation than the mature heart as assessed by functional criteria, and that defense mechanisms against stress caused by reactive oxygen metabolites are depleted more in mature hearts than immature and mature hearts and will provide a data base for development of strategies to improve myocardial preservation during ischemia and reperfusion.