Prostaglandin D2 effects and DP1/DP2 receptor distribution in guinea pig urinary bladder out‐flow region

The proximal urethra and urinary bladder trigone play important roles in continence. We have previously shown that PGD₂ is released from guinea pig bladder urothelium/suburothelium and can inhibit detrusor contractile responses. We presently wished to investigate PGD₂ actions in guinea pig out‐flow region and the distribution of DP₁/DP₂ receptors. The effects of PGD₂ on urothelium‐intact trigone and proximal urethra contractility were studied in organ bath experiments. Expression of DP₁/DP₂ receptor proteins was analysed by western blot. Immunohistochemistry was used to identify distribution of DP₁/DP₂ receptors. PGD₂ in a dose‐dependent manner inhibited trigone contractions induced by electrical field stimulation (EFS) and inhibited spontaneous contractions of the proximal urethra. PGD₂ was equally (trigone) or slightly less potent (urethra) compared with PGE₂. Expression of DP₁ and DP₂ receptors was found in male guinea pig bladder trigone, neck and proximal urethra. In the trigone and proximal urethra, DP₁ receptors were found on the membrane of smooth muscle cells and weak immunoreactivty was observed in the urothelium. DP₂ receptors were distributed more widespread, weakly and evenly in the urothelium and smooth muscles. Inhibitory effects by PGD₂ on motor activity of guinea pig trigone and proximal urethra are consistent with finding DP₁ and DP₂ receptors located in the urothelium and smooth muscle cells of the trigone and proximal urethra, and PGD₂ may therefore be a modulator of the bladder out‐flow region, possibly having a function in regulation of micturition and a role in overactive bladder syndrome.     

Ion channels of the mammalian urethra

The mammalian urethra is a muscular tube responsible for ensuring that urine remains in the urinary bladder until urination. In order to prevent involuntary urine leakage, the urethral musculature must be capable of constricting the urethral lumen to an extent that exceeds bladder intravesicular pressure during the urine-filling phase. The main challenge in anti-incontinence treatments involves selectively-controlling the excitability of the smooth muscles in the lower urinary tract. Almost all strategies to battle urinary incontinence involve targeting the bladder and as a result, this tissue has been the focus for the majority of research and development efforts. There is now increasing recognition of the value of targeting the urethral musculature in the treatment and management of urinary incontinence. Newly-identified and characterized ion channels and pathways in the smooth muscle of the urethra provides a range of potential therapeutic targets for the treatment of urinary incontinence. This review provides a summary of the current state of knowledge of the ion channels discovered in urethral smooth muscle cells that regulate their excitability.     

Systematic analyses of murine masculinization processes based on genital sex differentiation parameters

Murine reproductive tissues of the external genitalia and perineum develop with remarkably distinctive characteristics in males and females. Although many researches on such mouse organ development have been reported, there are still limited parameters that evaluate the developmental sexual differences of external genitalia and perineum. Furthermore, elucidation of the recent developmental signals for the external genitalia and perineum requires up‐to‐date knowledge of gene functions in reproductive science. To promote researches on reproductive organ formation, establishment of parameters for the androgen‐mediated formation of external genitalia and perineum is essential. In this study, we propose genital sex differentiation parameters (GSDP), a set of developmental parameters based on systematic three‐dimensional tissue reconstruction and cumulative histological analyses. We define the sexual differences of external genitalia and perineum by GSDP through analyzing mouse models, androgen inhibitor‐induced feminization experiments and Mafb mutant mouse with defective urethral differentiation. The urethral parameters displayed prominent reduction by the androgen inhibitor (finasteride) treatment. However, genital tubercle (GT) size parameters were not affected by such treatment. These results indicated that sensitivity to dihydrotestosterone was different between embryonic GT size and urethral formation. Furthermore, we evaluated the extent of urethral defects of Mafb mutant mice by GSDP. Thus, GSDP is a set of useful parameters to define the sexual differences during external genitalia and perineum development.     

Age-dependent changes in particulate and soluble guanylyl cyclase activities in urinary tract smooth muscle

Regional and age specific differences are observed in the sodium nitroprusside induced relaxation responses in the urinary tract. To clarify these differences, guanylyl cyclase activity is assayed in particulate and soluble fractions from the ureter, bladder dome, and urethra of young (11-18 days), adult (90-100 days), and old adult (2-3 years) guinea pigs. The rank order of soluble guanylyl cyclase activities is urethra = ureter > bladder dome with the largest decreases with aging occurring in the bladder. Atrial natriuretic factor (10-7 M) increases particulate guanylyl cyclase activity in the three tissues at all ages tested, with the activity being highest in the ureter. ATP (0.5 mM) activates particulate guanylyl cyclase in the ureter, bladder and urethra of old adult guinea pigs, and enhances atrial natriuretic factor induced activation of particulate guanylyl cyclase in all tissues and at all ages tested. The higher levels of soluble guanylyl cyclase activity in the urethra and ureter compared to the bladder parallel sodium nitroprusside induced relaxation in these tissues.     

Ion channels of the mammalian urethra

The mammalian urethra is a muscular tube responsible for ensuring that urine remains in the urinary bladder until urination. In order to prevent involuntary urine leakage, the urethral musculature must be capable of constricting the urethral lumen to an extent that exceeds bladder intravesicular pressure during the urine-filling phase. The main challenge in anti-incontinence treatments involves selectively-controlling the excitability of the smooth muscles in the lower urinary tract. Almost all strategies to battle urinary incontinence involve targeting the bladder and as a result, this tissue has been the focus for the majority of research and development efforts. There is now increasing recognition of the value of targeting the urethral musculature in the treatment and management of urinary incontinence. Newly-identified and characterized ion channels and pathways in the smooth muscle of the urethra provides a range of potential therapeutic targets for the treatment of urinary incontinence. This review provides a summary of the current state of knowledge of the ion channels discovered in urethral smooth muscle cells that regulate their excitability.