Decreased cardiac energy supply is likely of pathophysiologic significance in the failing cardiovascular system. Energetic efficiency (work for a given oxygen utilization) limits the ability of the heart to pump blood to the circulation both at rest and during times of stress. Oxidative stress, an imbalance between the formation of reactive oxygen species and antioxidant defenses, has been implicated in the development of heart failure not only by direct toxicity but also by altering metabolic pathways. We have recently shown that inhibition of xanthine oxidase (XO), an enzyme that produces superoxide during purine metabolism, profoundly enhances myocardial mechanoenergetic efficiency (the ratio of myocardial work to oxygen consumed) in an animal model of heart failure. This observation is consistent with in vitro findings that XO inhibition augments LV trabecular muscle force generation for a given amount of calcium entry into the cytoplasm. These data support a contributory role for oxidant stress in reducing cardiac myocardial energy utilization. The purpose of the studies in this proposal is to test the hypothesis that the XO pathway inhibits myocardial energetic efficiency by elaborating reactive oxygen species. Experiments will be conducted in conscious animals instrumented to measure LV work and oxygen consumption. We will first determine the contribution and biochemical mechanism of XO to the heart failure-associated increase in oxidative stress. In order to clarify the mechanism of allopurinol action and to assess the participation of another important signaling molecule (nitric oxide) to cardiac energetics, we will test the predictions that other antioxidants mimic, and that inhibition of nitric oxide attenuates the energetic effect of allopurinol. Finally and most importantly, we will determine whether XO inhibition prevents the development of LV dysfunction and whether the beneficial effects of XO inhibition in heart failure are due to its antioxidant properties. These studies are designed to define new mechanisms by which oxidant stress influences integrated cardiovascular performance in heart failure. The results of these studies will clarify pathophysiologic consequences of oxidant stress in heart failure and may have therapeutic implications for humans.
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