Halothane-anesthetized rabbit: a new experimental model to test the effects of besipirdine and duloxetine on lower urinary tract function.
BACKGROUND
The effects of besipirdine and its main metabolite, HP-748, as well as duloxetine and tomoxetine in the lower urinary tract (LUT) were studied using in vitro and in vivo techniques.


METHODS
For in vivo studies, besipirdine or duloxetine effects on cystometric parameters and striated sphincter electromyographic (SS-EMG) activity were investigated. On the isolated urethra, norepinephrine (NE) concentration-response curves (CRC) were performed in the presence of besipirdine, duloxetine or tomoxetine. Moreover, CRC to HP-748 were constructed in the absence or presence of prazosin. Potency (pEC(50)) and maximal responses (E(max)) were determined.


RESULTS
Besipirdine at 1, 3 and 5 mg/kg intravenously (i.v.) induced a significant increase in SS-EMG activity (250, 273 and 241%, respectively), bladder capacity (172, 197, and 235%, respectively), intercontraction interval (ICI; 208, 242, and 400%, respectively), and residual volume (181, 191, and 236%, respectively). Duloxetine at 2 mg/kg i.v. increased significantly SS-EMG activity (219%), micturition volume (222%), and ICI (205%). In the isolated urethra, besipirdine, tomoxetine and duloxetine significantly displaced to the left the NE CRC. In addition, HP-748 induced contraction of the isolated urethra with a pEC(50) of 5.89 and an E(max) of 37%.


CONCLUSIONS
These data support the potential of besipirdine as a new drug for LUT dysfunctions such as stress and mixed urinary incontinence.
Fundación Jiménez Díaz, Madrid, Spain. francisco.perez @ nanodrugs.es
Francisco C
FC
Pérez-Martínez
Remigio
R
Vela-Navarrete
Julio
J
Virseda
Ana V
AV
Ocaña
Philippe
P
Lluel
Moèz
M
Rekik
Hugues
H
Bienaymé
Jacques
J
Ferté
Pierre
P
Attali
Stefano
S
Palea
D000758:Anesthesia / Q000379:methods*; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D004576:Electromyography / Q000379:methods; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D012189:Retrospective Studies; D013876:Thiophenes / Q000494:pharmacology*; D014551:Urinary Tract / Q000187:drug effects*; D014552:Urinary Tract Infections / Q000188:drug therapy*; D014563:Urodynamics
D000777:Anesthetics; D007211:Indoles; D011437:Propylamines; D011725:Pyridines; D013876:Thiophenes; D000069445:Atomoxetine Hydrochloride; D000068736:Duloxetine Hydrochloride; C074872:besipirdine; D006221:Halothane; D009638:Norepinephrine; D011224:Prazosin