In the present study, the effects of systemic injection of radiographic contrast media (RCM) on vascular permeability was examined in various tissues of rats and the involvement of mast cell histamine in the RCM-induced vascular hyperpermeability subsequently determined. Both ionic (amidotrizoate) and non-ionic RCM (iohexol) enhanced vascular permeability specifically in lungs, as assessed by the extravasation of Evans blue (EB) dye. Another ionic RCM, ioxaglate, also markedly increased pulmonary vascular permeability and decreased pulmonary histamine content, whereby the extent of the reduction correlated well with the vascular hyperpermeability. Depletion of mast cells by prior treatment with compound 48/80 markedly attenuated the ioxaglate-induced enhancement of EB extravasation. The ioxaglate-increased extravasation was also inhibited by the mast cell stabilizer sodium cromoglicate and histamine H(1) and H(2) receptor antagonists. In isolated rat pulmonary mast cells, ioxaglate induced the concentration-dependent release of beta-hexosaminidase, an index of mast cell degranulation. The present findings thus show clearly that RCM causes the degradation of pulmonary mast cells and the resultant release of histamine that in turn increases vascular permeability by stimulating histamine H(1) and H(2) receptors.