The aim of this study was to investigate the effect of a moderate degree of hypoxia on coronary vascular permeability to various lipophobic solutes. Using the multiple indicator dilution method the permeability-surface area (PS) products were determined for 125I-albumin, 125I-insulin and 57Co-cyanocobalamin in perfused rat hearts (flow ≈10 ml·min-1 •g-1) either with well-oxygenated (pO2 ≈ 96 kPa) or hypoxic (pO2 ≈ 45 kPa) solutions. The PS products for albumin, insulin and cyanocobalamin during the well-oxygenated equilibration period were 0.20 ± 0.03, 0.29 ± 0.06 and 2.0 ± 0.3 ml·min-1.g-1 (mean ± SE), respectively, relative to 131I-n-globulin. The PS products for these solutes 15 min after the induction of hypoxia were 1.3 ± 0.3,0.8 ± 0.1 (p 0.05), respectively. In hearts perfused with well-oxygenated solution for 75 min, the PS products for these solutes remained stable throughout the period of the study. Electron-microscopic examination of hypoxic tissues showed the presence of endothelial gaps of approximately 1 µm which were underlined by an intact basal lamina. We conclude that a moderate degree of hypoxia produces a large increase in permeability of albumin and insulin but has no effect on the PS products for cyanocobalamin and that the endothelial gaps are the likely mechanism of the observed increas