Modeling of transendothelial transport

Abstract

Capillary-tissue exchange of inert hydrophilic solutes in the heart occurs through aqueous channels, the clefts between endothelial cells (ECs). For adenosine (and other vasoactive agents and substrates), there is also transport across the plasmalemma of the ECs. The multiple-indicator dilution technique comparing tracer adenosine flux with that of 9-beta-D-arabinofuranosylhypoxanthine (an analog that is not transported by the nucleoside carrier) can be used to estimate the conductance of the facilitated transport mechanism, which is equivalent to a permeability-surface area product. Analysis by using a model of exchanges among capillary, EC, interstitium, and myocardial cells suggests that the abluminal surface of the ECs is also highly permeable to adenosine. The inference is that ECs may be an important component of a system for adenosine exchange and regulation in the heart.

Figure 1

A) Coronary outflow dilution curves obtained from an isolated perfused guinea pig heart after a pulse injection of [¹⁴C]adenosine and two reference tracers, ¹³¹I-labeled albumin (remaining intravascular) and araH (remaining extracellular), at a flow F_s of 8.0 ml/(g · min). The model solutions (continuous lines) fitted to the data (symbols) describe the flow heterogeneity (dispersion relative to the mean = 46%, approximated by using seven parallel paths), the permeation of adenosine and araH through clefts between ECs (PS_g = 2.27 ml/(g · min)), and entry into interstitial space ($V_{\mathrm{isf}}^{\prime }$ = 0.2 ml/g). Other parameters for adenosine are: endothelial luminal surface PS_ecl = 6.0 ml/(g · min); abluminal surface PS_eca = 41 ml/(g · min); intraendothelial consumption G_ec = 116 ml/(g · min); parenchymal cell (myocyte) PS_pc = 4.7 ml/(g · min); volume $V_{\mathrm{pc}}^{\prime }$ = 0.3 ml/g; and myocyte consumption G_pc = 4.8 ml/g. B) Sensitivity functions for the parameters. The following scaling factors multiplied the S_p(t) values for the illustration: for PS_g 0.5, PS_ecl 0.45, PS_eca 177.5, PS_pc 47.0, $V_{\mathrm{isf}}^{\prime }$ 81.0, $V_{\mathrm{ec}}^{\prime }$ 275.0, $V_{\mathrm{pc}}^{\prime }$ 8200.0, G_ec 210.0, G_pc 2550.0.