The overall goal of this project is to provide vital information required for the formulation of a new conceptual framework for understanding the mechanisms by which oxygen is supplied to tissue. The current concepts are essentially slight modifications of Krogh's simplistic model of a single capillary supplying a specific cylinder of tissue (25). While his model provides a useful beginning, several important aspects of oxygen supply are neglected. Our recent observations of considerable oxygen exchange among microvessels (14,45) is in marked contrast to Krogh's idea of the capillaries being the sole source of oxygen supply. In addition, although the oxygen tension gradient between blood and tissue is important for oxygen transfer, it may not be the sole factor responsible for the adequate oxygenation of the tissue. It thus becomes imperative to change our conceptual framework. We must further investigate the numerous complex mechanisms responsible for the maintenance of oxygen supply under a broad range of conditions. Two hypotheses are to be tested in this project. The first is that oxygen content is an important regulator of oxygen exchange under conditions of a severely limited oxygen supply relative to demand. The second is that one mechanism by which oxygen supply to tissue is maintained under a wide range of conditions, is by an alteration in the localization of diffusive oxygen transfer. Experiments will be performed in the hamster cheek pouch retractor muscle. We will utilize a left-shift of the oxyhemoglobin dissociation curve (achieved by the chronic, short-term administration of sodium cyanate) to alter the relationship between oxygen tension and oxygen content. This change in hemoglobin oxygen affinity along with systemic hypoxia and isovolemic hemodilution will provide a broad range of oxygen supply conditions enabling us to specifically address our hypotheses. Data on capillary oxygen transport, both hemodynamic and oxygenation parameters will be obtained at specific locations within the capillary network using Ln vivo video microscopy and computer-aided image analysis techniques. In conjunction with the capillary data, information on the levels of oxygenation in the pre and postcapillary network will be obtained using fluorescently labeled red blood cells and PO2 microelectrodes positioned either on the wall of small arterioles or within first order arterioles and venules depending on the specific aim being addressed. These studies will provide vital information on the various interacting mechanisms responsible for the adequate supply of oxygen to tissue under a broad spectrum of oxygen supply conditions. Our understanding of these mechanisms will not only provide us with a better conceptual picture of tissue oxygenation but will aid our understanding of the factors responsible for the impairment in peripheral oxygen utilization frequently encountered clinically.
