REGULATION OF SINGLE CAPILLARY PERMEABILITY PROPERTIES

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Short term regulation of solute exchange, a process dependent on microvessel permeability, surface area, blood flow, and pressure, is a complex process. The complexity became evident when it w as shown that the capillary barrier was a dynamic structure responsive to a variety of stimuli and that the endothelial cell (EC) was both sensor and mechanotransducer in the regulation of vascular tone. In light of these data the present study was designed to evaluate the role of ECs in the regulation of exchange. The central hypothesis is that the exchange barrier, especially the EC, rapidly and selectively mediates changes in permeability to solute in response to changes in the local environment. The aims are to measure small solute and protein flux, Js, by microfluorometry in plasma perfused microvessels in the frog and hamster mesentery: 1) as a function of perfusion pressure, following assessment of in situ shear stress and following changes in shear stress to determine whether flow in the microvessel defines basal permeability to solute. From the Js data the transport coefficients, solute permeability (Pd) and solvent drag Jv(1-sigma)), will be calculated. The HYPOTHESIS is that Js will correlate with in situ shear stress, specifically small solute permeability and macromolecule solvent drag will increase with increasing shear stress. 2) under basal conditions and again during perfusion with a set of vasodilators to determine whether permeability responses to EC-dependent and EC-independent vasodilators are equivalent for solutes of differing size. The HYPOTHESIS is that the dilators will increase Js and because dilators evoke different cell-mediated changes in barrier structure, the js changes will have distinct spatial and temporal signatures. 3) under control conditions, again during perfusion with atrial natriuretic peptide, ANP, and third time with the ANP following a change in shear stress to determine whether mirovessel flow history modifies the magnitude of the response to a selected vasodilator and vice versa. The HYPOTHESIS is that the Js changes induced by ANP attenuate changes induced by shear-stress and not the reverse. The long term aim of this research is to determine the mechanisms whereby microvessel permeability properties vary in response to physiological stimuli. The ability to regulate both barrier properties and Starling Forces facilitates rapid, selective, localized changes in exchange in exchange capacity to maintain homeostasis. The longer term and the very fast homeostatic mechanisms have been studied extensively and are better understood. Little work has been carried out on the regulatory features in the short term (minutes to hours) control of fluid balance at the level of the exchange barrier.