(Verbatim from the application): Advances in the treatment of ischemic heart disease and myocardial infarction are critically dependent upon knowledge of pathological changes that occur in the coronary resistance circulation, the vascular bed that governs blood flow. This is a proposal for research into the mechanisms underlying changes that occur in the control of coronary blood flow during hypoxia and the role of oxygen in nitric oxide metabolism. The target of the research is the coronary resistance, or microvascular, circulation. The principal theme of the research is to a) define mechanisms of nitric oxide (NO) regulation of vascular tone in response to low partial pressures of oxygen using an in vivo model, b) to understand mechanisms of reciprocal regulation of NO and prostanoids which, in turn, impact upon regulation and preservation of coronary blood flow, and c) to elucidate the mechanisms whereby oxygen tension alters NO and prostanoid control of flow-mediated vasomotion.
The first aim will establish physiological changes that occur during hypoxia in vivo and the role of nitric oxide in mediating those changes. The research will utilize an in vivo catheter-based porcine model that allows selective perfusion of coronary arteries with extracorporeally oxygenated blood equilibrated with selected partial pressures of oxygen and will allow research into the effect of hypoxia on coronary vascular resistance and flow velocity. The detailed research into mechanisms will build upon the physiological mediated changes in NO and prostacyclin production as well as the mechanisms of reciprocal regulation of NO and prostanoids by negative feedback inhibition will be done in a cultured cell model. Experiments are also designed to increase our understanding of a recently discovered NO positive feedback mechanism. Experiments determining the cellular response to hypoxia during flow will use a model allowing culture of endothelium under pulsatile flow conditions. Research into the molecular basis for adaptations to hypoxia will primarily employ Western and Northern blots. Pharmacologic antagonists of NO and prostanoid synthesis will be used to discover mechanisms controlling microvascular tone. With this approach, it is likely that the research will yield important new insights into the complex mechanisms responsible for the control of microvascular tone and coronary blood flow during hypoxia and periods of hypoperfusion, such as occurs during ischemia, reperfusion, and acute myocardial infarction.
