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The effects of ionic and nonionic contrast media on rabbit venous endothelium were examined. In anesthetized animals, caudal mesenteric veins were exposed and perfused with the ionic contrast medium, diatrizoate, and the nonionic contrast media iopromide and iotrolan for 2 minutes at 5 mL/minute. Control animals were similarly perfused with physiologic saline or a 23% sorbitol solution. The specimens were fixed in situ by perfusing 4% glutaraldehyde, and ultrathin stained sections were examined with an electron microscope. The hyperosmolar contrast medium diatrizoate produced shrinkage in cell cytoplasm and in nuclear material. There also were minor structural alterations in endoplasmic reticulum and widening of intercellular junctions. The nonionic contrast media iotrolan and iopromide caused mild to moderate changes in endothelial cells. Sorbitol infusion, however, affected venous endothelium more intensely than the ionic and nonionic contrast media, suggesting hyperosmolality as the causal factor in endothelial damage.