No abstract

A method is described for studying transcapillary diffusion of K42 in isolated perfused muscles of dogs. Blood flow and arteriovenous K42 differences are measured and blood-tissue clearance calculated by the Fick principle. A theoretical relation between blood flow and blood-tissue clearance is developed for a uniform circulation characterized by a constant permeability—surface area product (PS). The experimental observations conform reasonably closely to prediction. However, systematic variation in measured PS product with changes in blood flow and vascular resistance indicate that the capillary circulation is not uniform.

Morphological and physiological studies indicate multiple routes for transport across capillary endothelium. However, the identification of the morphological counterparts of specific transport processes (or the assignment of specific transport roles to morphologically identifiable pathways) has been only partly achieved: the contribution of endothelial cell membranes to transport of water and small, lipid-insoluble molecules needs to be evaluated. The identification of the "small pore" pathway for water and lipid-insoluble molecules with the intercellular junctions still remains questionable. The contributions to total macromolecular transport of junctions, single vesicles (pinocytosis, cytopempsis), chains of vesicles, and fenestrae are not yet known.

Steady-state 125I-labeled rat serum albumin (125I-labeled RSA) concentration in plasma was maintained by intravenous infusion of tracer for 72-168 h with an implanted osmotic pump. At the end of the infusion period, the rat was anesthetized and nephrectomized, and extracellular fluid was equilibrated with intravenous 51Cr-labeled EDTA for 4 h. Five minutes before final plasma and tissue sampling, 131I-labeled bovine serum albumin (131I-labeled BSA) was injected intravenously as a plasma volume marker. Samples of skin, muscle, tendon, and intestine were assayed for all three tracers. Apparent distribution volumes were calculated as tissue tracer content/plasma tracer concentration. Interstitial fluid volume (Vi) was calculated as V51Cr-EDTA-V131I-BSA. Steady-state extravascular distribution of 125I-labeled RSA as plasma equivalent volume (Va,p) was calculated as V125I-RSA-V131I-BSA. Steady-state interstitial fluid concentrations of 125I-labeled RSA in skin, muscles, and tendon were measured with nylon wicks implanted postmortem, and steady-state interstitial albumin distribution volumes were recalculated as wick-fluid equivalent volumes (Va,w). Relative albumin exclusion fraction (Ve/Vi) was calculated as 1-Va,w/Vi. For skin and muscle, steady-state 125I-labeled RSA tissue concentrations were reached at 72 h. Ve/Vi for albumin averaged 26% in hindlimb muscle, 41% in hindlimb skin, 30% in back skin, 39% in tail skin, and 54% in tail tendon. For muscle, Ve/Vi corresponds to expectation if all tissue collagen and hyaluronan is dispersed in the interstitium. However, for skin and tendon, albumin exclusion is considerably lower than expected on this basis, suggesting that much of their collagen is organized into dense bundles of fibers containing no fluid accessible to 51Cr-labeled EDTA or 125I-labeled RSA.

Starling's hypothesis ascribes fluid movements across capillary walls to the interaction of hydrostatic and colloid osmotic forces. For 90 years it has been recognized as the basis of plasma-to-interstitial fluid balance. Its original statement was based on the notion of capillary impermeability to plasma proteins. However, as knowledge of transcapillary exchange of plasma proteins developed, its formulation was progressively modified to allow for protein transport and for interaction of protein transport with volume flow. The most important aspects of the conceptual evolution of Starling's hypothesis are reviewed in the text of this lecture.