Myocardial ischemia, whether disease-related (infarction) or iatrogenic (during cardiac surgery) is a major medical problem. The overall hypothesis of this proposal is that cytptoxic oxygen metaolites, including superoxide anion (SA), hydrogen peroxide (HP) and hydroxyl radical are important contributors to ischemic damage: the heart is both a significant source and target of their damaging actions. Precedence for this has come, in part, from a previous physiologic study of the phenomena thaat are implicated here. This study uses isolated rabbit hearts, perfused with physologic buffer, then made ischemic and reperfused, to assess biochemically two potential sources of these metabolites (mitochondria, xanthine oxidase) and two organelles [mitochondria, microsome (SR)] thought to be important sites of their damaging effects.
Specific aims (questions) are: (1) Does ischemia decrease mitochondrial capacity to degrade SA and/or HP? (2) Does ischemia increase mitochondrial generation of SA and/or HP during respiration or Ca accumulation? (3) Does ischemia cause conversion of xanthine dehydrogenase to the oxidase form in the rabbit, as shown in the dog? (4) Is the protective effect of allopurinol due to its suppression of SA generation by xanthine that might be expected from free radical pathology? (6) Do in vitro oxygen radical-generating systems impair function of mitochondria and SR similar to changes seen after i situ ischemia? (7) Which of the above changes occur, and how great are they, after ischemia/reperfusion compared to after ischemia alone? How does length of ischemia affect them? and (8) does hypothermia, which is used clinically to reduce intraoperative cardiac damage, specifically affect oxygen radical-mediate pathology? This study should add significant new information about the pathophysiology of ischemia, and should help identify new interventions to suppress damage.
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