Vascular function is integrated with the needs of the organism by neural and humoral control processes. Control processes intrinsic to the tissue allow the functional demands of individual organs to be accommodated with minimal disturbances to the organism as a whole. These local control systems modulate blood flow into the tissue, distribution of flow within the tissue, and diffusion distances. There is substantial evidence that altered function of the regulatory process leads to such diverse pathological changes as hypertension and sickle cell crisis, and diabetic angiopathy. Oxygen plays a pivotal role in the regulatory process, either as a substrate whose delivery or concentration is regulated, or as a key substrate in metabolism. We have recently developed new techniques which permit us to carry out studies of the local control process at the level of the microcirculation. We can measure convective transport of oxygen in vessels as small as 15 microns in diameter, and we can study the reactivity of arterioles in vitro to a variety of substances including oxygen. In the research program proposed in this grant application, we will use these techniques to study the role of oxygen in the regulatory process in skeletal muscle microcirculation. We will: (1) quantitate red cell and oxygen delivery and the distribution of these through the microcirculation; (2) examine the relative contributions of alterations in oxygen delivery and oxygen distribution ot the regulatory process; (3) investigate the relative contributions of small arteries, large arterioles, small arterioles, and capillaries to flow regulation and to modulation of diffusion distance; (4) ascertain the cell type responsible for the oxygen sensitivity of arterioles; and (5) test the hypothesis that cytochrome P450 and metabolites of arachidonic acid act as sensors mediating the action of oxygen. These experiments will be carried out on the cheek pouch as well as the cremaster, tibialis anterior, and gracilis muscles of the golden hamster.
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