The significance of periurethral fibrosis and the change of nitric oxide synthase containing nerves in the urethra of diabetic rats

Purpose: We have previously demonstrated that increased urethral resistance was more prominent in diabetic rats than in controls. This may result from a compressive obstruction such as damage of the urethral nerve containing nitric oxide. Another possible cause for urethral obstruction could be a constrictive obstruction such as a periurethral fibrosis. In the present study, we investigated the changes in the expression of nitric oxide synthase (NOS) isoforms (compressive obstruction) and collagen subtypes (constrictive obstruction) in the urethral tissues of non-insulin dependent diabetic rats. Materials and Methods: Thirty-six male Sprague-Dawley rats (18 diabetic rats and 18 control rats), bred from birth, were included in this study. Diabetes mellitus was induced by intraperitoneal administration of streptozotocin (90mg/kg) on the second day after birth. Urethral tissues were harvested at 12, 24 and 36 weeks after induction of diabetes and were stained for neuronal NOS (nNOS) and Masson trichrome. We also performed reverse transcriptase-polymerase chain reaction or Western blot analysis to evaluate mRNA or protein expression of NOS isoforms and collagen subtypes in the urethral tissues. Results: Immunohistochemical staining and Western blot analysis of nNOS revealed that the immunoreactivity and nNOS expression in the urethra was lower in the diabetic rats than in the controls. The Masson trichrome staining showed that there was urethral fibrosis in the diabetic rats. The mRNA or protein expression of collagen subtypes, especially type I collagen, were higher in the diabetic rat urethra than in the controls. Conclusions: These data suggest that the increased urethral resistance in diabetic rats may be attributable to a decrease in the urethral nNOS expression and an increase in collagen content. Urethral dysfunction as well as a cystopathy may play an important role in the pathogenesis of diabetes-induced voiding dysfunction.