选择性雄激素受体调节剂（SARM）GSK2849466A 对去卵巢诱导雌激素缺乏大鼠压力性尿失禁和膀胱活动的影响。
Effects of a selective androgen receptor modulator (SARM), GSK2849466A, on stress urinary incontinence and bladder activity in rats with ovariectomy-induced oestrogen deficiency.
机构信息
Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.
Muscle Metabolism DPU, GlaxoSmithKline, King of Prussia, PA, USA.
出版信息
BJU Int. 2020 Jun;125(6):911-919. doi: 10.1111/bju.15022. Epub 2020 Mar 20.
OBJECTIVES
To report the effect of a selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX).
MATERIALS AND METHODS
Female Sprague-Dawley rats with bilateral OVX were used. Rats were divided into five groups; sham operated, vehicle-treated OVX, low-dose SARM-treated OVX (GSK2849466A: 0.005 mg/kg/day, per os [p.o.]), high-dose SARM-treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT)-treated OVX (1 mg/kg/day, subcutaneous) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze-induced continence reflex using microtransducer-tipped catheter methods, sneeze-induced leak-point pressure, and continuous cystometry measurements, followed by histological analyses of urethral tissues.
RESULTS
(i) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (ii) Low-dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A-URS), partially reversing OVX-induced SUI during sneezing. (iii) High-dose SARM treatment reversed decreases in both UBP and A-URS, more effectively preventing SUI during sneezing. (iv) DHT treatment only restored A-URS without affecting UBP, partially preventing OVX-induced SUI during sneezing. (v) The high-dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (vi) SARM treatment did not affect bladder function in sham or OVX rats.
CONCLUSION
Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT, without affecting bladder function, by enhancing smooth- and striated muscle-mediated urethral function under stress conditions such as sneezing.
目的
报道选择性雄激素受体调节剂（SARMs）对双侧卵巢切除（OVX）诱导的压力性尿失禁（SUI）大鼠模型尿道控尿机制的影响。
材料和方法
使用雌性 Sprague-Dawley 大鼠双侧 OVX。将大鼠分为五组：假手术组、载体处理 OVX 组、低剂量 SARM 处理 OVX 组（GSK2849466A：0.005mg/kg/天，口服[po. ]）、高剂量 SARM 处理 OVX 组（GSK2849466A：0.03mg/kg/天，po.）和二氢睾酮（DHT）处理 OVX 组（1mg/kg/天，皮下）。在 SARM 治疗 4 周或 DHT 治疗 3 周（OVX 后 6 周）后，使用微传感器尖端导管方法评估大鼠打喷嚏诱发的控尿反射、打喷嚏诱发的漏尿点压和连续膀胱测量，随后对尿道组织进行组织学分析。
结果
（i）OVX 在 6 周后显著损害尿道控尿功能，导致打喷嚏时发生 SUI。（ii）低剂量 SARM 治疗恢复了尿道基础压（UBP），而不影响打喷嚏时尿道反应的幅度（A-URS），部分逆转了打喷嚏时 OVX 诱导的 SUI。（iii）高剂量 SARM 治疗逆转了 UBP 和 A-URS 的降低，更有效地预防了打喷嚏时的 SUI。（iv）DHT 治疗仅恢复了 A-URS，而不影响 UBP，部分预防了打喷嚏时 OVX 诱导的 SUI。（v）高剂量 SARM 治疗诱导了尿道周围横纹肌和平滑肌的肥大。（vi）SARM 治疗对假手术或 OVX 大鼠的膀胱功能没有影响。
结论
与 DHT 相比，SARM 治疗可能是治疗 SUI 的更有效方法，通过在打喷嚏等应激条件下增强平滑肌和横纹肌介导的尿道功能，而不影响膀胱功能。
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