title: Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats.
abstract: Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.
authors.affiliation: Division of Neuroscience Research, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Katofiasc
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nissen
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.forename: Karl B
authors.initials: KB
authors.lastname: Thor
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology; D000283:Administration, Intravesical; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D002415:Cats / Q000502:physiology*; D003511:Cyclohexanols / Q000494:pharmacology*; D000068736:Duloxetine Hydrochloride; D004576:Electromyography; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008719:Methiothepin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014521:Urethra / Q000187:drug effects* / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D000069470:Venlafaxine Hydrochloride
chemical_list: D019342:Acetic Acid; D018759:Adrenergic Uptake Inhibitors; D003511:Cyclohexanols; D000068736:Duloxetine Hydrochloride; D005473:Fluoxetine; D008719:Methiothepin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; D000069470:Venlafaxine Hydrochloride