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: Jeremy Reese, Zhiying Xiao, Zeyad Schwen, Yosuke Matsuta, Bing Shen, Jicheng Wang, James R Roppolo, William C de Groat, Changfeng Tai
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 349 Issue 3 Pg. 402-7 (Jun 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 24667547 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adrenergic Uptake Inhibitors
• Piperazines
• Pyridines
• Serotonin Antagonists
• Thiophenes
• Serotonin
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• Duloxetine Hydrochloride
• Acetic Acid

Topics

• Acetic Acid (administration & dosage)
• Adrenergic Uptake Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Animals
• Cats
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Duloxetine Hydrochloride
• Electric Stimulation
• Female
• Male
• Piperazines (administration & dosage, pharmacology, therapeutic use)
• Pudendal Nerve (drug effects, physiology)
• Pyridines (administration & dosage, pharmacology, therapeutic use)
• Serotonin (metabolism)
• Serotonin Antagonists (administration & dosage, pharmacology, therapeutic use)
• Thiophenes (administration & dosage, pharmacology, therapeutic use)
• Urinary Bladder, Overactive (chemically induced, drug therapy, metabolism)