AJP - Heart and Circulatory Physiology, Vol 264, Issue 6 1798-H1809, Copyright © 1993 by American Physiological Society

ARTICLES

Thrombin and bradykinin initiate discrete endothelial solute permeability mechanisms

R. C. Schaeffer Jr, F. Gong, M. S. Bitrick Jr and T. L. Smith
Benjamin W. Zweifach Microcirculation Laboratories, Veterans Affairs Medical Center, Tucson, Arizona 85723.

This study documents the discrete solute permeability mechanisms associated with physiologically high concentrations of human alpha-thrombin and bradykinin stimulation of bovine pulmonary artery endothelial cell (BPAEC) monolayers using fluorescein isothiocyanate-hydroxyethyl starch macromolecules. Agonist-induced alterations of intracellular free calcium ([Ca2+]i) using fura-2 acetoxymethyl ester were also measured. BPAEC monolayers showed restricted diffusion consistent with a small-pore (approximately 150 A) radius under baseline conditions. Thrombin produced a major increase in monolayer permeability that was greatest for solute molecular radii (ae) > 100 A. This effect was associated with the exposure of the large (approximately 2,000 A) pores of the filter support by 50- to 1,050-microns2 open areas between approximately 0.5% of the adjacent endothelial cells. This heterogeneous endothelial barrier of parallel large- and small-pore transport pathways permitted solute convection with free diffusion across a few large pores to dominate the restricted diffusion of most apparently unperturbed endothelial junctions. Bradykinin produced a small, transient elevation in monolayer permeability to ae < 35 A, consistent with an increase in the number of small pores or a decrease in path length of this transport pathway. The bradykinin- and thrombin-induced peak elevations in [Ca2+]i were inversely associated with the degree of increased monolayer solute permeability, and enzymatically inhibited thrombin produced none of these effects. These data show that bradykinin and human alpha-thrombin represent two distinct classes of endothelial cell agonists that initiate discrete solute permeability mechanisms.

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