Dept. of Urology, Univ. of Pittsburgh, 700 Kaufmann Bldg., Pittsburgh, PA 15213.
Am J Physiol Renal Physiol. 2013 Dec 15;305(12):F1663-8. doi: 10.1152/ajprenal.00523.2013. Epub 2013 Oct 23.
The purpose of this study was to determine whether duloxetine [a serotonin (5-HT)-norepinephrine reuptake inhibitor] combined with transcutaneous foot stimulation or WAY-100635 (a 5-HT1A antagonist) can enhance inhibition of bladder overactivity in cats. Cystometrograms were performed on eight cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, foot stimulation (5 Hz) was applied via transcutaneous pad electrodes to the right hindfoot at two and four times the threshold intensity for inducing a toe twitch. Duloxetine (0.003-3 mg/kg) was administered intravenously to determine the effect of combination treatment. After the 3 mg/kg dose of duloxetine, WAY-100635 (0.5 mg/kg) was given intravenously. AA irritation significantly (P < 0.0001) reduced bladder capacity to 42.7 ± 7.4% of the saline control capacity. Foot stimulation alone at both two and four times the threshold intensity significantly (P < 0.0001) inhibited bladder overactivity and increased bladder capacity to 66.7 ± 6.3% and 85.7 ± 6.5% of the saline control, respectively. Duloxetine alone dose dependently inhibited bladder overactivity and completely restored bladder capacity to the saline control (109 ± 15.5%) at 3 mg/kg. Although duloxetine combined with foot stimulation did not further enhance inhibition, WAY-100635 (0.5 mg/kg) given after 3 mg/kg duloxetine further increased (P = 0.008) bladder capacity to 162.2 ± 22.5% of the saline control. Although duloxetine and foot stimulation independently inhibited bladder overactivity, combined treatment did not enhance inhibition. Duloxetine combined with WAY-100635, however, synergistically enhanced bladder inhibition, indicating a potential novel treatment for overactive bladder if duloxetine is combined with a 5-HT1A receptor antagonist drug.
本研究旨在确定度洛西汀（一种 5-HT-去甲肾上腺素再摄取抑制剂）联合经皮足部刺激或 WAY-100635（一种 5-HT1A 拮抗剂）是否可以增强对猫膀胱过度活动的抑制作用。在α-氯醛糖麻醉下对 8 只猫进行膀胱测压描记术，通过输注生理盐水和 0.25%乙酸（AA）来诱导膀胱过度活动。为了抑制膀胱过度活动，通过经皮垫电极将足部刺激（5 Hz）施加于右后脚，刺激强度为引起脚趾抽搐的 2 倍和 4 倍。静脉内给予度洛西汀（0.003-3 mg/kg）以确定联合治疗的效果。给予 3 mg/kg 度洛西汀后，静脉内给予 WAY-100635（0.5 mg/kg）。AA 刺激显著（P < 0.0001）降低膀胱容量至生理盐水对照容量的 42.7 ± 7.4%。单独使用足部刺激 2 倍和 4 倍阈值强度均显著（P < 0.0001）抑制膀胱过度活动，并将膀胱容量分别增加至生理盐水对照的 66.7 ± 6.3%和 85.7 ± 6.5%。度洛西汀单独使用时呈剂量依赖性抑制膀胱过度活动，并将膀胱容量完全恢复至生理盐水对照（109 ± 15.5%）。尽管度洛西汀联合足部刺激并未进一步增强抑制作用，但在给予 3 mg/kg 度洛西汀后给予 WAY-100635（0.5 mg/kg）进一步增加（P = 0.008）膀胱容量至生理盐水对照的 162.2 ± 22.5%。尽管度洛西汀和足部刺激独立抑制膀胱过度活动，但联合治疗并未增强抑制作用。然而，度洛西汀与 WAY-100635 联合使用可协同增强膀胱抑制作用，表明如果将度洛西汀与 5-HT1A 受体拮抗剂药物联合使用，可能为治疗膀胱过度活动提供一种新的治疗方法。
