Possible mechanistic roles of anatomical and functional vascular changes in rat urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Anatomical and functional vascular changes during rat urinary bladder carcinogenesis were studied by scanning electron microscopy of vascular casts, transmission electron microscopy of bladder capillaries, and fractional distributions of 51Cr-erythrocytes, 125I-human serum albumin, and 86RbCl which were used to determine vascular volume, permeability, and perfusion. Histopathological changes and focal capillary changes in vascular casts were measured quantitatively by an image analyzer. Male Wistar rats received 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 8 weeks and were then maintained on tap water without BBN for an additional 32 weeks. Simple hyperplasia was first seen at Week 2. The percentage of the area of hyperplastic epithelium increased to about 95% by Week 8 and then decreased to 4 to 6% at Weeks 20 or 40. Papillary or nodular hyperplasia was first seen at Week 6. The percentage of the area of papillary or nodular hyperplasia increased with time to 31.0% at Week 40. Papillary transitional-cell carcinomas were found from Week 20, increasing with time, and their incidence was 100% after Week 35. Vascular cast diameters of normal-looking capillaries were larger during than after BBN treatment. Type 3 vascular proliferations were found beneath papillary or nodular hyperplasia and cancer. Capillaries beneath simple hyperplasia and type 3 capillaries beneath capillary or nodular hyperplasia and cancers were fenestrated and dilated. Changes in vascular volume were independent of changes in permeability and perfusion. Best-fit curve analyses showed the maximum vascular volume at 8 weeks and minimum at 25 weeks, and the permeability maxima at 4 and 25 weeks with minima at 15 and 32 weeks. While 86Rb values correlated 125I values (r = 0.58), they were unstable in intermediate time periods. Changes of vascular volume were coincident initially with increased areas of dilated capillaries beneath simple hyperplasia and later with areas of type 3 capillary proliferation beneath papillary or nodular hyperplasia and cancer. Changes of vascular permeability were related to inflammation indices throughout the study. Increases in permeability were coincident with fenestrated capillaries beneath simple hyperplasia in early stages, and subsequently with fenestrated type 3 capillaries beneath papillary or nodular hyperplasia and cancer. BBN appears to cause alterations in vascular volume via induction of capillary dilation and also possibly by enhancing the responsiveness of host endothelium to angiogenic stimulation from neoplastic or preneoplastic tissues.