Local mechanisms, that act upon the microvasculature, control blood flow to various organs to meet their metabolic demands. There is substantial evidence that disturbances in the microcirculation or local control mechanism cause or may be caused by disease states such as hypertension and diabetes. Before the influence of disease states on the microcirculation can be understood, we must first understand the normal physiology of the system. It is well established that the oxygen is involved in the regulation of microvascular function. However, the precise role in the local control of blood flow in unclear because we do not know 1) the location of the sensor that mediates microvascular oxygen reactivity and 2.) the mechanism of action of oxygen on the microvasculature. These two areas are the focus of this proposal. We have the unique ability to critically evaluate hypotheses concerning oxygen and control of microvascular function by the use of state of the art techniques such as intravital videomicroscopy, in situ microvessel perfusion, preparation of parenchyma free arterioles and measurement of PO2 with oxygen microelectrodes. These methods will be used in the research proposed in this application to determine the location of the sensor that mediates arteriolar oxygen reactivity and to the examine the mechanism of action of oxygen on arterioles. We will 1.) test the hypothesis that the oxygen sensors that mediate arteriolar oxygen reactivity are located either in venules or are distributed sparsely along the vasculature. 2.) test the hypothesis that either the 5-lipoxygenase and leukotrienes or cytochrome P-450 are involved in arteriolar oxygen reactivity and characterize conduction of oxygen induced constrictions and compare these responses with conducted responses induced by norepinephrine and leukotrienes, and 3.) determine if there are significant regional and species differences in O2 reactivity in terms of the location of the sensor and the mechanism of action. These experiments will be carried out on the cheek pouch of golden hamsters and cremaster muscles of golden hamsters and Sprague-Dawley rats.
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