Elucidation on mechanisms of vanilloid and cannabinoid functions in the urogenital afferent neurotransmissions

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Backaround of the study on the significance of epithelial sodium channel (ENaC) in the mechanism inducing overactive bladder :Overactive bladder (OAB) is the symptom-based syndrome which was newly defined by the International Continence Society in 2002, and is a storage dysfunction exhibiting urinary urgency as an essential symptom. The mechanism inducing urinary urgency has not been revealed, although it has been speculated that it is involved in the abnormality in the afferent transmission. One has noted the significance on the role of unmyelinated C-fibers in which vanilloid receptors (VR1, VRL1) are largely expressed under pathologic conditions such as spinal cord injury, while the essence of mechanoceptors which convey urinary sensations is unknown. The recent studies demonstrated that the urothelium produced transmitters including ATP, influencing the transmission in the bladder sensory (Fry, C.H. : Urology, 2004). Thus, we examined the epithelial sodium channel (ENaC), one of th … More e candidates involved in the mechanosensory transduction in the bladder.Materials and Methods :1)Study in the human : Urothelia from patients without bladder outlet obstruction and with benign prostatic hyperplasia presenting OAB symptoms, were used. The expression of ENaC proteins was examined by immunohistofluorescent staining using anti-ENaC subunit polyclonal antibodies, and the ENaC genes expression was assessed by a quantitative RT-PCR.2)Study in the rat (in vitro) : Urothelia from female rats without bladder outlet obstruction and with partial urethral obstruction, were used. The expression of ENaC proteins was examined by immunohistofluorescent staining using anti-ENaC subunit polyclonal antibodies, and the ENaC genes expression was assessed by a quantitative RT-PCR.3)Study in the rat (in vivo) : Detrusor contractility and intermicturition interval were evaluated during cystometry. The effects of amiloride, an ENaC inhibitor, on these parameters were also examined.Results :1)Study in the human : The expression of proteins for ENaC subunits (α, β, γ) was detected in the human urinary bladder. The expression levels of each ENaC subunit mRNA in obstructed bladders were significantly greater than those in controls (Urology, 64 : 1255-1260, 2004).2)Study in the rat (in vitro) : The expression of proteins for ENaC subunits (α, β, γ) was detected in the rat urinary bladder, although the expression levels of each subunit mRNA were not quantitatively different between bladders with and without bladder outlet obstruction3)Amiloride, an ENaC inhibitor, did not change the detrusor contractility, whereas it markedly increased the intermicturition interval.Conclusions and Discussion :The studies revealed a remarkable species difference between the human and rat bladders with obstructed urethra in the expression levels of ENaC subunits (α, β, γ) mRNA, while these suggested the possibility that ENaC was involved in the induction of overactive bladder. Less