Research (I.K., A.I., M.K., K.Y.), Formerly, Japan Development Center (H.N., T.K.), Formerly, Pharmaceutical Research Division (S.O.), and Takeda Development Center Japan (Y.N.), Takeda Pharmaceutical Company Ltd., Fujisawa and Osaka, Japan; and Formerly, Takeda Development Center Europe Ltd., London, United Kingdom (G.O.)
Research (I.K., A.I., M.K., K.Y.), Formerly, Japan Development Center (H.N., T.K.), Formerly, Pharmaceutical Research Division (S.O.), and Takeda Development Center Japan (Y.N.), Takeda Pharmaceutical Company Ltd., Fujisawa and Osaka, Japan; and Formerly, Takeda Development Center Europe Ltd., London, United Kingdom (G.O.).
J Pharmacol Exp Ther. 2021 Aug;378(2):60-68. doi: 10.1124/jpet.121.000573. Epub 2021 Apr 9.
Under healthy conditions, more than one urethra-closing reflex, including both bladder afferent-independent and -dependent actions, function during momentary elevation of intravesical (bladder) pressure to prevent urinary incontinence In the current study, the effects of a novel selective 5-hydroxytryptamine type 2C (5-HT) receptor agonist, TAK-233, on evoked momentary urethra-closing functions were investigated in female rats and humans to elucidate 5-HT receptor functions. In anesthetized female rats, TAK-233 dose-dependently and significantly increased urethral resistance during sneezing in rats with distended vaginas and bilaterally transected pelvic nerves. The drug also dose-dependently and significantly increased urethral resistance during momentary intravesical pressure elevation by electrical stimulation of abdominal muscles in rats with a transected spinal cord at the T8-T9 level and intact pelvic nerves. The increased effects observed during electrical stimulation were abolished by either an intravenously administered selective 5-HT receptor antagonist, SB 242084, or bilateral transection of the pelvic nerves or somatic nerves innervating the external urethral sphincter and pelvic floor muscles. In the spinal cord-transected and pelvic nerve-intact rats, TAK-233 enlarged the urethra-closing responses induced by both passive and abrupt intravesical pressure elevation, measured by a microtip transducer located in the middle urethra. Additionally, the effects of TAK-233 on the stimulus threshold of urethral contractile responses induced by transcranial magnetic stimulation were investigated in healthy female volunteers. The drug dose-dependently and significantly lowered this stimulus threshold, indicating an increased sensitivity of the response. These results demonstrate that 5-HT receptor stimulation enhances the evoked momentary urethra-closing functions in both female rats and humans. SIGNIFICANCE STATEMENT: 5-hydroxytryptamine (serotonin) type 2C (5-HT) receptor stimulation by TAK-233 enhanced urethral resistance in rats during an evoked momentary event in which the bladder afferent-independent or -dependent reflex functions via striated muscle-mediated mechanisms. The increases in sensitivity of transcranial magnetic stimulation-evoked urethral contractile responses in healthy female subjects indicates that this mechanism also functions in humans. The evoked momentary conditions activating these reflexes provide a suitable model to demonstrate the effects of 5-HT receptor stimulation.
在健康条件下，超过一种尿道闭合反射，包括膀胱传入神经独立和依赖的动作，在瞬间升高膀胱内压时发挥作用，以防止尿失禁。在目前的研究中，研究了一种新型选择性 5-羟色胺 2C（5-HT）受体激动剂 TAK-233 对雌性大鼠和人类诱发瞬间尿道闭合功能的影响，以阐明 5-HT 受体功能。在麻醉雌性大鼠中，TAK-233 剂量依赖性地显著增加了阴道扩张和双侧盆神经横切大鼠打喷嚏时的尿道阻力。该药物还剂量依赖性地显著增加了 T8-T9 水平脊髓横切和完整盆神经的大鼠通过腹部肌肉电刺激瞬间升高膀胱内压时的尿道阻力。在电刺激过程中观察到的增加作用被静脉内给予的选择性 5-HT 受体拮抗剂 SB 242084 或双侧盆神经或支配尿道外括约肌和骨盆底肌肉的躯体神经横切所消除。在脊髓横切和盆神经完整的大鼠中，TAK-233 扩大了由被动和突然升高的膀胱内压引起的尿道闭合反应，由位于尿道中段的微尖端换能器测量。此外，还研究了 TAK-233 对健康女性志愿者经颅磁刺激引起的尿道收缩反应刺激阈值的影响。该药物剂量依赖性地显著降低了该刺激阈值，表明反应的敏感性增加。这些结果表明，5-HT 受体刺激增强了雌性大鼠和人类中诱发的瞬间尿道闭合功能。 意义陈述：TAK-233 通过 5-HT 受体刺激增强了大鼠在诱发的瞬间事件中的尿道阻力，在该事件中，通过横纹肌介导的机制，膀胱传入神经独立或依赖的反射功能发挥作用。健康女性受试者经颅磁刺激诱发的尿道收缩反应敏感性的增加表明该机制也在人类中起作用。激活这些反射的诱发瞬间条件提供了一个合适的模型来展示 5-HT 受体刺激的效果。
