Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats.
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.
Katofiasc
Mary A
MA
Division of Neuroscience Research, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
Nissen
Jeffrey
J
Audia
James E
JE
Thor
Karl B
KB
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
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