Localization of constitutive nitric oxide synthase isoforms and the nitric oxide target enzyme soluble guanylyl cyclase in the human bladder

Purpose: Nitric oxide is a free radical gas synthesized from L-arginine by a family of isoenzymes called nitric oxide synthase that has an important role in smooth muscle relaxation. L-arginine, the substrate for nitric. oxide synthase, may be beneficial under pathophysiological conditions in the bladder, as in interstitial cystitis. We determined the localization of nitric oxide synthase and the target enzyme of NO, soluble guanylyl cyclase, in the human bladder. Materials and Methods: Benign bladder tissues were obtained from 18 patients with localized superficial bladder tumors undergoing transurethral bladder resection. Histochemical nicotinamide adenine dinucleotide phosphate-diaphorase staining, nitric oxide synthase immunohistochemical testing and soluble guanylyl cyclase immunoreactivity studies were performed in all benign tissue specimens. Results: A different pattern of nitric oxide synthase expression was confirmed by nicotinamide adenine dinucleotide phosphate-diaphorase staining and immunohistochemical testing for endothelial and neuronal nitric oxide synthase. In addition to endothelial nitric oxide synthase expression, detrusor smooth muscle was recognized as an important location of endothelial nitric oxide synthase, while the urothelium had only small endothelial nitric oxide synthase positive cell clusters. Neuronal nitric oxide synthase expression was only found in nitrinergic fibers of the submucosal surface and between muscle cells. Detrusor and vascular smooth muscle as well as interstitial cells, nerve fibers and transitional epithelium were recognized as targets of nitric oxide, as shown by soluble guanylyl cyclase expression. Conclusions: The distribution of constitutive nitric oxide synthase isoforms and soluble guanylyl cyclase provides evidence of nitric oxide-cyclic guanosine monophosphate mediated regulation of detrusor smooth muscle relaxation, neurotransmission and blood flow. Furthermore, the urothelium may also be a target of nitric oxide.