Increasing Effects of Selective 5-Hydroxytryptamine Type 2C Receptor Stimulation on Evoked Momentary Urethral Closure in Female Rats and Humans
| العنوان: | Increasing Effects of Selective 5-Hydroxytryptamine Type 2C Receptor Stimulation on Evoked Momentary Urethral Closure in Female Rats and Humans |
|---|---|
| المؤلفون: | Masako Kuno, Yuya Nishiyama, Akio Imanishi, Hiroshi Nagata, Takuya Kato, Izumi Kamo, Satoshi Okanishi, Kyoko Yoshikawa, Gale O'Connell |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 378:60-68 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Agonist, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Urinary Bladder, Stimulation, chemistry.chemical_compound, Internal medicine, Receptor, Serotonin, 5-HT2C, medicine, Animals, Humans, Pharmacology, business.industry, Urethral sphincter, Receptor antagonist, Rats, Transcranial magnetic stimulation, Urethra, medicine.anatomical_structure, Endocrinology, chemistry, Reflex, Molecular Medicine, Female, business, SB-242084 |
| الوصف: | Under healthy condition, 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-HT2C) receptor agonist, TAK-233, on evoked momentary urethra-closing functions were investigated in female rats and humans to elucidate 5-HT2C receptor functions. In anesthetized female rats, TAK-233 dose-dependently and significantly increased the 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 T8-9 level and intact pelvic nerves. The increased effects observed during electrical stimulation were abolished by either an intravenously administered selective 5-HT2C 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 micro-tip 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-HT2C receptor stimulation enhances the evoked momentary urethra-closing functions in both female rats and humans. Significance Statement 5-hydroxytryptamine (serotonin) type 2C (5-HT2C) 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 exerting effects of 5-HT2C receptor stimulation. |
| تدمد: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.121.000573 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1c0c4500cd14bcf3cdeb2f1d63adc193 https://doi.org/10.1124/jpet.121.000573 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1c0c4500cd14bcf3cdeb2f1d63adc193 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
|---|---|
| DOI: | 10.1124/jpet.121.000573 |