Alpha2-adrenoceptor blockade potentiates the effect of duloxetine on sneeze induced urethral continence reflex in rats.
OBJECTIVE
Serotonin and norepinephrine reuptake inhibitors such as duloxetine have clinical efficacy for stress urinary incontinence. However, the therapeutic dose of duloxetine is often associated with unwanted side effects. We examined whether combined alpha(2)-adrenoceptor antagonists could decrease the duloxetine dose due to synergistic effects.


METHODS
We used normal female rats and rats with stress urinary incontinence induced by vaginal distention. Urethral responses were measured using a microtransducer tipped catheter. We evaluated the effect of low dose duloxetine (0.1 mg/kg), alpha(2)-adrenoceptor antagonists (idazoxan or yohimbine) and sequential administration of drugs on urethral pressure response amplitude during sneezing and urethral baseline pressure. Sneeze induced leak point pressure was also measured.


RESULTS
In normal and vaginally distended rats low dose duloxetine did not alter urethral pressure response amplitude during sneezing but it significantly increased urethral baseline pressure. When low dose duloxetine was co-applied with alpha(2)-adrenoceptor antagonists, urethral pressure response amplitude during sneezing was significantly increased. In all 7 vaginally distended rats leakage was observed during sneezing. After low dose duloxetine administration fluid leakage still occurred during sneezing. However, after low dose duloxetine and idazoxan co-administration fluid leakage disappeared in 2 of 7 rats and sneeze induced leak point pressure was significantly increased in the remaining incontinent rats with vaginal distention.


CONCLUSIONS
Findings support the concept that combination therapy with alpha(2)-adrenoceptor antagonists may be an effective, novel strategy to reinforce the clinical efficacy of serotonin and norepinephrine reuptake inhibitors for stress urinary incontinence.
Kitta
Takeya
T
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Miyazato
Minoru
M
Chancellor
Michael B
MB
de Groat
William C
WC
Nonomura
Katsuya
K
Yoshimura
Naoki
N
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D000068736:Duloxetine Hydrochloride; D005260:Female; D019329:Idazoxan / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012912:Sneezing / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*; D014521:Urethra / Q000503:physiopathology*; D014550:Urinary Incontinence, Stress / Q000503:physiopathology*; D015016:Yohimbine / Q000494:pharmacology*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000068736:Duloxetine Hydrochloride; D019329:Idazoxan; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; D015016:Yohimbine