Aims:To investigate functional roles of transient receptor potential melastatin 8 (TRPM8) channels, we determined if TRPM8 channel antagonist could inhibit the detrusor overactivity induced by menthol spray and low temperature. Methods:Two days prior to cystometric investigation, the bladder of 10-week-old Spague-Dawley rats were cannulated. After 20 min of baseline cystometry period at room temperature (RT: 27±2°C), the TRPM8 channel antagonist, N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)pi-perazine-1-carboxamide (BCTC), or vehicle, was administered through a jugular vein catheter (n=6). A 90% menthol solution, which was TRPM8 channel agonist, was sprayed onto rump to leg skin once every 5 min for 20 min, and then cystometric measurements were repeated.After a 30-min recovery period, the rats were intravenously administered 0.1 μmol/kg BCTC. Five minutes later, they were again sprayed, and then cystometric measurements were recorded. In separate experiments, cannulated rats were intravenously administered 0.001, 0.01, or 0.1μmol/kg BCTC (n=6 each dose) at RT. Five minutes later, they were transferred to expose low temperature (LT: 4±2°C). During LT exposure, the cystometric measurements were recorded for 20 min. Results:The rats sprayed with menthol exhibited the decrease of the voiding interval, micturition volume, and bladder capacity. After treatment of BCTC, the rats did not show these decreases. Exposure to LT elicited detrusor overactivity characterized with decreased voiding interval, micturition volume, and bladder capacity. However, at 0.01 and 0.1μmol/kg, BCTC inhibited the cold stress-induced detrusor overactivity.Conclusions: TRPM8 channels antagonist, BCTC, inhibited detrusor overactivity in rats sprayed with menthol.Furthermore, the BCTC inhibited the cold stress-induced detrusor overactivity. Therefore, TRPM8 channels expressing within the skin mediate detrusor overactivity elicited by menthol spray and exposure to low temperature.

THC-002 inhibited cold stress-induced detrusor overactivity resulting from decreasing skin temperature. Therefore, THC-002 might provide resistance to cold stress-exacerbated lower urinary tract symptoms.

The purpose of this study was to determine whether bone marrow-derived cells implanted into radiation-injured urinary bladders could reconstruct functional bladder tissues. The pelvic region of anesthetized female SpragueDawley (SD) rats was irradiated with 2 Gy once a week for 5 weeks. After the last irradiation, the rats were maintained for 2 weeks. Bone marrow cells were harvested from the femurs of donor male green fluorescence protein (GFP)-transfected SD rats and cultured for 7 days. Two weeks after the last radiation exposure, the cultured adherent, proliferating bone marrow-derived cells were implanted into the walls of irradiated urinary bladders. For controls, cell-free solutions were similarly injected. Four weeks after donor cell or control implantations, cystometric, histological, and immunohistochemical investigations were performed. Two weeks after the last irradiation, the smooth muscle layers and nerve fibers of the irradiated urinary bladders were disorganized. The proportions of smooth muscle layer and nerve fiber areas were significantly decreased compared with sham-irradiated urinary bladders. In addition, the remaining smooth muscle cells within the irradiated urinary bladders expressed P4HB, an indicator of collagen synthesis. In the cystometric investigations, the voiding interval of irradiated rats was irregularly prolonged, 7.92 -1.09 min, and the residual volume, 0.13 -0.03 mL, was significantly higher compared with the sham-irradiated rats (5.50 -0.43 mL and 0.05 -0.01 mL). After 4 weeks, the smooth muscle layers and nerve fibers in the cell-free control urinary bladders remained similar to the preimplanted irradiated urinary bladders; however, the cell-implanted urinary bladders contained reconstructed smooth muscle layers and nerve fibers, the proportions of each were significantly higher than those in the cell-free injected controls. The expression of P4HB within the cell-implanted urinary bladders decreased. Some GFPpositive implanted cells differentiated into smooth muscle-and nerve-like cells and became organized into the reconstructed tissues. The voiding interval of the cell-implanted rats, 5.46 -0.33 min, was regular and similar to that of the sham-irradiated rats, and significantly less than that of the cell-free injected controls, 7.39 -0.54 min. The residual volume, 0.04 -0.01 mL, was similar to that of the sham-irradiated rats and significantly decreased compared with that of the cell-free injected controls, 0.15 -0.05 mL. Therefore, the implantation of bone marrowderived cells is a potentially useful treatment for radiotherapy-induced urinary dysfunctions.

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