(Verbatim from the application): Ischemic heart disease is the leading cause of death in Western cultures. Ischemia is caused by an imbalance in the heart's consumption of oxygen and the delivery of oxygen by the coronary circulation. Under normal conditions, the heart avoids ischemia by tightly matching myocardial oxygen consumption to coronary blood flow. To date, the mechanistic basis of this matching remains unknown. Many coronary vasodilators have been implicated in this process but conclusions have been confounded by the repeated observation that inhibitors of a single dilator do not impair physiologic adjustments in coronary blood flow. Several recent studies indicate a different paradigm, one in which coronary blood flow is not controlled by a singe vasodilator but by a network of redundant vasodilators. When one vasodilator in this network is inhibited, another increases their contribution such that coronary blood flow is preserved. In this regard, several studies have suggested a link between nitric oxide (NO) and adenosine in moderating coronary blood flow. Specifically, when NO is inhibited, the contribution from adenosine may increase, serving as a mechanism of compensatory vasodilation. The mechanism by which this occurs, however, remains unclear. The application tests the novel idea that NO directly reduces response to adenosine and that, when NO production is inhibited, responses to adenosine are potentiated. We find that, in animals chronically treated with the eNOS inhibitor L-NAME, the contribution of adenosine to metabolic hyperemia is increased. Based on this evidence, we hypothesize that adenosine plays an important role as a compensatory vasodilator when NO production is impaired. This hypothesis will be tested in 3 specific aims. 1) We hypothesize that increased vasodilator sensitivity to adenosine is an important compensatory mechanism that maintains normal coronary blood flow if NO production is chronically impaired. To complete this aim, we will examine coronary blood flow, microvascular diameter, interstitial adenosine concentrations and vascular reactivity to receptor blockade on basal and hyperemic flow I both normal and NO-impaired animals. 2) We hypothesize that adenosine A2a receptor mediated coronary vasodilation is augmented by chronic impairment of NO production. We will test this hypothesis by determining whether the dilation to adenosine A2a receptor stimulation is enhanced in coronary arterioles in vitro. We will assess the specificity of this augmentation by determining if alternative dilator pathways are also augmented by chronic reductions in NO production. (3) We hypothesize that, in the context or chronic impairment of NO production, the increased vasodilatory sensitivity to adenosine is associated with an increased expression of adenosine A2a receptors. We will test this hypothesis by using comparative RT-PCR analysis of individual coronary arterioles and determining if A2a receptors are upregulated without changes in other adenosine signaling molecules. Taken together, these studies will provide a thorough examination of the role and mechanisms of action of adenosine as a compensatory vasodilator during chronic NO impairment. This mechanism may contribute to the ability of the coronary circulation to maintain cardiac perfusion and avoid ischemia during the early stages of coronary artery disease when NO-dependent dilation is compromised.
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