The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction.
OBJECTIVE
To investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle.


METHODS
BOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.).


RESULTS
IC485 (5-50 mg/kg i.v.) decreased the number and amplitude of non-voiding contractions during the storage phase by 63-88% and 49-83%, respectively; IC485 also increased bladder capacity by 28-37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non-voiding contractions by 38-74% and 29-44%, respectively, and increased bladder capacity by 19-51%. Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35-67% and 19-34%, respectively.


CONCLUSIONS
Both IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed non-voiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO.
Kaiho
Yasuhiro
Y
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Nishiguchi
Jun
J
Kwon
Dong Duek
DD
Chancellor
Michael B
MB
Arai
Yoichi
Y
Snyder
Peter B
PB
Yoshimura
Naoki
N
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology*; D005260:Female; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D010665:Phenylpropanolamine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects*; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D014563:Urodynamics
D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010726:Phosphodiesterase Inhibitors; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate