Capillary water and solute transport have been regarded to be passive processes. Recent single capillary studies from our laboratory suggest vascular permeability can be actively regulated under normal conditions. The central hypothesis is that the barrier separating circulating blood from tissue is not a static partition but possesses the ability to rapidly and selectively alter water and solute permeability in response to changes in the local environment. Our overall aim is to determine the mechanisms whereby microvascular permeability properties are altered in response to physiological stimuli. These studies will be conducted in individually perfused capillaries of amphibia and mammalia where hydrostatic and osmotic pressures were controlled, perfusate and suffusate solutions defined and vascular surface area is constant. The mammalian studies on hamster (mesocricetus auratus) mesenteric microvessel, will test whether exchange vessel properties are similar to those in the amphibian model, frog (rana pipiens) mesenteric microvessels. Thus, testing the generality of the results. Additional studies, with isolated endothelia, are proposed to bridge our single vessel findings with those at the cellular level and will test whether the endothelial cell is the component controlling barrier function. Transvascular water movement will be measured by the modified Landis technique; solute movement will be measured by microfluorometry. In paired experiments transport will be assessed in vessels classified by flow pattern as arteriolar, true or venular capillaries, first under control conditions, then under specified test conditions. During the next five years we will test directly the following hypotheses: 1) Exchange vessels are maintained at an intermediate (activated) state and possess a continuum of sensitivity thus, multiple factors determine the level of vessel activation as well as the degree to which a vessel may alter permeability, thus 2) The luminal trans-membrane flux of calcium across the endothelial cell surface is the major determinant of activation state, and 3) Humoral agents acutely and reversibly modify the permeability properties of an activated vessel. Resolution of these hypotheses will provide additional insight into the mechanisms of short term or acute control of whole body water and solute distribution in the exchange vasculature. The longer term humeral and the very fast neurally mediated homeostatic mechanisms have been better studied. Very little work has been done to investigate the regulatory features in the short term (minutes to hours) regulation of fluid balance at the level of the exchange barrier. The ability to regulate microvessel exchange properties, along with the ability to alter Starling Forces, would allow for rapid, selective and local changes in the exchange capacity to maintain homeostasis.
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