Genitourinary Biology, Pfizer Global Research and Development, Sandwich, UK.
BJU Int. 2012 Jul;110(2 Pt 2):E113-7. doi: 10.1111/j.1464-410X.2011.10756.x. Epub 2011 Dec 22.
Preclinically, studies investigating urethral function have shown that the clinical benefit of agents such as duloxetine may partly reflect increases in urethral striated muscle activity via a central mode of action. Duloxetine has been shown to inhibit the presynaptic reuptake of 5-HT and norepinephrine in Onuf's nucleus, leading to an increased activity of pudendal motor neurones and a subsequent increase in the strength of urethral sphincter contractions. Preclinical studies have postulated a role for both 5-HT(2C) receptors and 5-HT(2A) receptors in external urethral sphincter (EUS) function, with differences between species that may reflect the differing physiological roles of the EUS in different preclinical species. The present study therefore aimed to investigate the 5-HT receptor subtype involved in EUS function in the guinea-pig. The in vivo data reported in the present study suggest that the effects of clinical agents used to treat stress urinary incontinence, which enhance serotonergic drive, may be mediated, at least in part, via 5-HT(2C) receptors.
To elucidate the subtype of 5-HT receptor involved in urethral function using a preclinical model of urethral function.
The effects of the 5-HT(2C) agonist Ro 600-175 were investigated by measuring the urethral pressure profile in anaesthetized guinea-pigs together with antagonists at 5-HT(2A) , 5-HT(2B) and 5-HT(2C) receptor subtypes.
Ro 600-175 increased peak urethral pressure in a dose-dependent manner. This effect was reversed by the selective 5-HT(2C) antagonist SB 242084. Neither the 5-HT(2A) antagonist MDL 100907, nor the 5-HT(2B) antagonist SB 240741 had any significant effect on the response.
The clinical benefit of drugs used to treat stress urinary incontinence through enhanced serotonergic and adrenergic drive may be mediated, at least in part, via 5-HT(2C) receptors. Selective 5-HT(2C) agonism increases urethral tone, and hence provides an opportunity for developing new pharmacotherapies for stress urinary incontinence with reduced side-effects.
在临床前研究中，研究表明，度洛西汀等药物的临床获益部分反映了通过中枢作用模式增加尿道横纹肌的活动。度洛西汀已被证明可抑制 Onuf 核内 5-HT 和去甲肾上腺素的突触前再摄取，导致阴部运动神经元的活动增加，随后尿道括约肌收缩的强度增加。临床前研究推测 5-HT（2C）受体和 5-HT（2A）受体在外尿道括约肌（EUS）功能中都有作用，不同物种之间的差异可能反映了 EUS 在不同临床前物种中的不同生理作用。因此，本研究旨在研究参与豚鼠尿道功能的 5-HT 受体亚型。本研究报告的体内数据表明，用于治疗压力性尿失禁的临床药物增强 5-羟色胺能驱动的作用可能至少部分通过 5-HT（2C）受体介导。
使用尿道功能的临床前模型阐明参与尿道功能的 5-HT 受体亚型。
通过测量麻醉豚鼠的尿道压力谱，研究 5-HT（2C）激动剂 Ro 600-175 的作用，同时研究 5-HT（2A）、5-HT（2B）和 5-HT（2C）受体亚型的拮抗剂。
Ro 600-175 以剂量依赖性方式增加尿道压力峰值。这种作用被选择性 5-HT（2C）拮抗剂 SB 242084 逆转。5-HT（2A）拮抗剂 MDL 100907 或 5-HT（2B）拮抗剂 SB 240741 均无明显作用。
通过增强 5-羟色胺能和肾上腺素能驱动来治疗压力性尿失禁的药物的临床获益可能至少部分通过 5-HT（2C）受体介导。选择性 5-HT（2C）激动剂增加尿道张力，因此为开发治疗压力性尿失禁的新药物治疗方法提供了机会，可减少副作用。
