The studies in this proposal are designed to provide insight into mechanisms by which responses of the coronary microvasculature can affect perfusion of ischemic myocardium. The goal of these studies is to define functional responses of the coronary resistance vessels in myocardial regions distal to a flow limiting coronary artery stenosis or in regions perfused by collateral channels that can influence the development of myocardial ischemia and which might be amenable to therapeutic intervention. Studies will be performed in chronically instrumented dogs in which coronary artery flow is measured with a Doppler flowmeter while regional systolic contractile function is assessed with ultrasonic microcrystals. Myocardial perfusion is measured with microspheres; aortic and coronary venous catheters will allow measurement of nitric oxide (NO) production by the coronary vasculature. Initial studies will determine whether exercise stimulates NO production, and whether exercise in the presence of a coronary stenosis which results in myocardial ischemia causes a further increase in NO production. A subsequent study will examine-interactions between metabolic coronary vasodilator mechanisms mediated by K+ATP channel opening and adenosine to determine whether blockade of metabolic vasodilator mechanisms augments coronary NO production. A second group of studies will examine responses of coronary resistance vessels which are perfused through collateral channels. Collateral vessel development will be induced with repeated brief coronary occlusions or by placement of an ameroid constrictor on the left anterior descending coronary artery. An initial study will determine whether ACIA-riboside can selectively increase adenosine production in collateralized myocardium, thereby augmenting perfusion of the collateral-dependent region during exercise. A second study will measure NO production by collateral vessels and distal coronary vasculature perfused by collaterals in vivo, to determine whether NO production is decreased in coronary vessels which are perfused through collateral channels. A third protocol will determine whether basal or stimulated NO production is decreased in coronary microvessels isolated from a collateral- dependent myocardial region. A final protocol will determine whether there is decreased expression of constitutive endothelial NO synthase mRNA or protein in the collateral-dependent region, and whether the collateral-dependent region demonstrates expression of inducible NO synthase mRNA or protein.
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