Effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on sneeze-induced urethral continence reflex in rats.
We investigated the effect of duloxetine, a norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor, on the neurally evoked urethral continence reflex induced by sneezing in rats. To clarify the role of noradrenergic and serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we examined the effect of duloxetine followed by intrathecal (it) methiothepin maleate (5-HT receptor and alpha1-adrenoceptor antagonist) or terazosin or idazoxan (selective alpha1- and alpha2-adrenoceptor antagonists, respectively). Amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal adult female rats and rats with SUI induced by vaginal distension (VD). In normal and VD rats, intravenous application of duloxetine (1 mg/kg) increased A-URS by 35% and 34% and UBP by 21% and 34%, respectively. Sneezing-induced fluid leakage from the urethral orifice was observed in VD rats but not in normal rats. S-LPP was increased from 39.1 to 92.2 cmH2O by intravenous duloxetine in incontinent VD rats. Duloxetine-mediated enhancement of A-URS was inhibited by terazosin but not methiothepin maleate (it). In addition, simultaneous intrathecal application of methiothepin and terazosin induced a reduction in A-URS during sneezing, which was not increased by intravenous duloxetine. However, the reduced A-URS after intrathecal application of methiothepin and terazosin returned to the control level when duloxetine (iv) was applied after intrathecal idazoxan administration. These results indicate that duloxetine can prevent SUI by facilitating noradrenergic and serotonergic systems in the spinal cord to enhance the sneeze-induced active urethral closure mechanism.
Miyazato
Minoru
M
Department. of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kaiho
Yasuhiro
Y
Kamo
Izumi
I
Chancellor
Michael B
MB
Sugaya
Kimio
K
de Groat
William C
WC
Yoshimura
Naoki
N
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000068736:Duloxetine Hydrochloride; D005260:Female; D019329:Idazoxan / Q000494:pharmacology; D008719:Methiothepin / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012912:Sneezing / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*; D014521:Urethra / Q000187:drug effects / Q000502:physiology*; D014550:Urinary Incontinence, Stress / Q000503:physiopathology*; D014621:Vagina / Q000503:physiopathology
D018759:Adrenergic Uptake Inhibitors; D000068736:Duloxetine Hydrochloride; D019329:Idazoxan; D008719:Methiothepin; D011224:Prazosin; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C041226:Terazosin