This project will explore the concept that certain interventions instituted at the time of a coronary occlusion can limit the amount of cardiac necrosis which will result. Although this has been, and continues to be, a controversial subject, recent evidence indicates that at least two drug classes may well possess this capability. These are the calcium antagonists and agents which suppress free radicals. Projects are proposed which will examine 6 specific aspects of this concept. The first project will examine the time course of regional wall function following a permanent coronary occlusion in both untreated dogs and those treated with allopurinol (an agent which markedly reduces infarct size in our dog model of permanent occlusion). We want to see if the salvage observed histolochemically, is accompanied by any mechanical benefit. In Project 2, we will define the conditions which promote the conversion of xanthine dehydrogenase to the free radical producing enzyme, xanthine oxidase. We are particularly interested in identifying agents (e.g., calcium antagonists or protease inhibitors) which might block this conversion since blockade should be therapeutic. Project 3 will test whether allopurinol's protection is wholly related to suppression of free radical production or if it may also involve conservation of phosphorylatable purines. In Project 4, we will perfuse a langendorf rat heart with an indicator for superoxide radicals. This model will be used to both identify conditions which enhance free radical production and interventions which suppress it. Another way to test whether the calcium antagonists might somehow involve suppression of free radical production is to see if combination with allopurinol gives an additive protection. This will be investigated in component 5. The last component will concentrate on perfecting a small animal model for assessment of infarct size limiting activity. Preliminary data indicates that a suitable region-at-risk type of assessment can be made in both the rat or the rabbit. In conclusion, we propose a series of experiments which should clarify the role of xanthine oxidase derived free radicals in infarcting myocardium and identify means for preventing that damage.
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