application): The broad, long-term objectives of this proposal are to investigate the mechanisms of oxygen (O2) transport and the limitations of O2 supply through microvascular networks in striated muscle during graded contractions.
The Specific Aims are: (1) To measure the drop in oxygen tension (PO2) from the red blood cell (RBC) to the sarcolemma and to evaluate the magnitude of extracellular (outside muscle fiber) O2 transport resistance; (2) To investigate the effect of heterogeneity of vascular geometry and hemodynamics on oxygenation parameters (intravascular PO2, Hb-O2 saturation, tissue PO2) at the level of small capillary networks supplied by a single terminal arteriole and of larger microvascular networks supplied by multiple arterioles, and to determine the degree to which this heterogeneity limits O2 supply. The research design is to measure plasma PO2, Hb-O2 saturation (SO2), tissue PO2 and hemodynamic variables (RBC velocity and RBC lineal density or hematocrit) in capillaries and small arterioles in electrically stimulated hamster retractor muscles using intravital microscopy and to analyze the resulting data using mathematical models for single capillaries, capillary networks and small arterioles. Plasma PO2 in arterioles and capillaries will be measured with the phosphorescence quenching technique; RBC velocity, microvessel hematocrit and SO2 in arterioles and capillaries will be measured with video densitometric and image analysis techniques. Tissue PO2 will be measured using sharpened microelectrodes. Experimental data on microvascular network geometry and hemodynamics will be used as an input in the mathematical model; the transport equations will be solved numerically. The model will predict intravascular SO2 and PO2 and tissue PO2 distributions. The model will be validated by statistical comparison of its predictions to the experimental data. This new validated mathematical model would serve as a basis and prototype for realistic mathematical models of O2 transport in different organs and tissues. The new knowledge from this study should enhance our understanding of the mechanisms of O2 supply during muscle contraction. The results of the project should provide answers to important questions regarding the roles of extracellular, particularly intracapillary, resistance and heterogeneity of oxygen supply as factors limiting normal function in tissues with high aerobic metabolism. The health-relatedness of this project is in understanding the limitations of O2 supply in tissues with high aerobic metabolism such as contracting skeletal muscle and heart. In disease states, structural, biophysical or biochemical changes in tissue affect the determinants of O2 supply; thus, it is important to identify these determinants and their role in the O2 transport processes.
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