Increasing Effects of Selective 5-Hydroxytryptamine Type 2C Receptor Stimulation on Evoked Momentary Urethral Closure in Female Rats and Humans

• Published in: The Journal of pharmacology and experimental therapeutics 2021-08, Vol.378 (2), p.60-68
• Main Authors: Kamo, Izumi, Nagata, Hiroshi, O'Connell, Gale, Kato, Takuya, Imanishi, Akio, Kuno, Masako, Okanishi, Satoshi, Yoshikawa, Kyoko, Nishiyama, Yuya
• Format: Article
• Language: English
• Subjects: Adult; Animals; Dose-Response Relationship, Drug; Electric Stimulation; Female; Humans; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C - drug effects; Serotonin 5-HT2 Receptor Agonists - pharmacology; Spinal Cord Injuries - physiopathology; Urethra - drug effects; Urethra - innervation; Urethra - physiology
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.121.000573

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 demonst