The influence of hypoxia on transvascular leakage in the isolated rat heart: quantitative and ultrastructural studies.

1. The multiple indicator dilution method was used to study the transvascular movement of gamma-globulin, bovine serum albumin, insulin and cyanocobalamin in the isolated rat heart. 2. Perfusion of the heart with well-oxygenated solution for 75 min (constant flow) did not produce a significant change either in the total area under the dilution curve or the 'leakage index' (an arbitrary measure of transvascular flux) for all the tracers. 3. Perfusion of the heart with hypoxic solution produced a significant increase in leakage of gamma-globulin of 38.6 +/- 18, 48.5 +/- 17.6, 60.5 +/- 24 and 58 +/- 20% after 15, 30, 45 and 60 min, respectively, compared with the well-oxygenated equilibration period. Permeability- surface area products (PS) for the smaller diffusible solutes, therefore, could not be estimated. 4. The flux of albumin, insulin and cyanocobalamin in response to hypoxia was similar to that of gamma-globulin. 5. Ultrastructural examination of well-oxygenated hearts revealed that Monastral Blue-labelled albumin remained within the lumen and that endothelial integrity remained intact. 6. Conversely biopsies from hypoxic hearts showed that the labelled albumin had passed to the interstitium through gaps (approximately 3 microns) in venular endothelium. 7. The results showed that, in intact hearts, hypoxia produced gaps in the endothelium of venules and that these gaps could be the possible route for transvascular leakage of macromolecules.