VASCULAR METABOLISM AND ITS RELATION TO FUNCTION

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DESCRIPTION: (adapted from the abstract) The overall goal of this application is to study the specific major classes of hypotheses which may underlie the vasodilatory effect of hypoxia in porcine coronary arteries (hypoxic vasodilatation). The specific, hypothetical, oxygen sensing areas to be studied would be intracellular calcium, changes in pH, alteration of calcium sensitivity of the contractile apparatus and limitation of metabolism and high energy phosphagens. The proposed studies will include measurements of the effect of hypoxia on intracellular calcium and pH using ratiometric fluorescent dye techniques and the relationship between intracellular calcium, myosin light chain phosphorylation and isometric force and the effect on metabolism and phosphagen profiles and content utilizing analytical isotachophoresis. The preliminary data carried out to date suggest that none of the major mechanisms previously proposed including the sodium pump, and ATP-dependent potassium channels, for example, actually underlie the hypoxic vasorelaxation in porcine coronary artery. In addition, initial evidence also suggests that with stimulation by KCL calcium does not change or is actually increased by hypoxia despite a decrease in isometric force. These results suggest the existence of a novel type of oxygen sensing mechanism in porcine coronary artery smooth muscle. In addition there are new data presented in the application which suggest that pH may strongly influence vessel response to hypoxia. In addition, these workers have identified three distinct types of endothelium-dependent oxygen sensing responses in the coronary artery and, their proposed studies therefore also include tests of the hypotheses that alterations of endothelial cell calcium, pH, or energy metabolism underlie these various endothelium dependent response to oxygen. The information is important not only to the basic understanding of vascular physiology but also developing a rational therapeutic approach to vascular pathology including vasospastic disease.