title: Effects of duloxetine and WAY100635 on pudendal inhibition of bladder overactivity in cats.
abstract: This study was aimed at determining the effect of duloxetine (a serotonin-norepinephrine reuptake inhibitor) on pudendal inhibition of bladder overactivity. Cystometrograms were performed on 15 cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, pudendal nerve stimulation (PNS) at 5 Hz was applied to the right pudendal nerve at two and four times the threshold (T) intensity for inducing anal twitch. Duloxetine (0.03-3 mg/kg) was administered intravenously to determine the effect on PNS inhibition. AA irritation significantly (P < 0.01) reduced bladder capacity to 27.9 ± 4.6% of saline control capacity. PNS alone at both 2T and 4T significantly (P < 0.01) inhibited bladder overactivity and increased bladder capacity to 83.6 ± 7.6% and 87.5 ± 7.7% of saline control, respectively. Duloxetine at low doses (0.03-0.3 mg/kg) caused a significant reduction in PNS inhibition without changing bladder capacity. However, at high doses (1-3 mg/kg) duloxetine significantly increased bladder capacity but still failed to enhance PNS inhibition. WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide; a 5-HT1A receptor antagonist, 0.5-1 mg/kg i.v.) reversed the suppressive effect of duloxetine on PNS inhibition and significantly (P < 0.05) increased the inhibitory effect of duloxetine on bladder overactivity but did not enhance the effect of PNS. These results indicate that activation of 5-HT1A autoreceptors on the serotonergic neurons in the raphe nucleus may suppress duloxetine and PNS inhibition, suggesting that the coadministration of a 5-HT1A antagonist drug might be useful in enhancing the efficacy of duloxetine alone and/or the additive effect of PNS-duloxetine combination for the treatment of overactive bladder symptoms.
authors.affiliation: Department of Urology (J.R., Z.X., Z.S., Y.M., B.S., J.W., C.T.) and Department of Pharmacology and Chemical Biology (J.R.R., W.C.D.G., C.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Urology, The Second Hospital, Shandong University, Jinan, People's Republic of China (Z.X.).
authors.forename: Jeremy
authors.initials: J
authors.lastname: Reese
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Xiao
authors.forename: Zeyad
authors.initials: Z
authors.lastname: Schwen
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsuta
authors.forename: Bing
authors.initials: B
authors.lastname: Shen
authors.forename: Jicheng
authors.initials: J
authors.lastname: Wang
authors.forename: James R
authors.initials: JR
authors.lastname: Roppolo
authors.forename: William C
authors.initials: WC
authors.lastname: de Groat
authors.forename: Changfeng
authors.initials: C
authors.lastname: Tai
mesh_terms: D019342:Acetic Acid / Q000008:administration & dosage; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002415:Cats; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068736:Duloxetine Hydrochloride; D004558:Electric Stimulation; D005260:Female; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D060525:Pudendal Nerve / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D013876:Thiophenes; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000068736:Duloxetine Hydrochloride; D019342:Acetic Acid