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

Abstract

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. CONCLUSIONBoth IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed nonvoiding 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. KEYWORDSbladder outlet obstruction, detrusor overactivity, rat, type 4 phosphodiesterase Study Type -Aetiology (case control) Level of Evidence 3b OBJECTIVETo 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. MATERIALS AND METHODSBOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO,

Animal model for the study of the relationship between lower urinary tract symptoms/bladder outlet obstruction and erectile dysfunction

“…Rats were fully anesthetized during the procedure and no body movement or distress was observed during EFS. The best ICP value was divided by simultaneous mean AP (ICP/AP) 19–21 …”

Detrusor myocyte activity and afferent signaling

“…PDE 4 inhibitors reduced the in vitro contractile responses of guinea pig, 133 suppressed rhythmic bladder contractions of the isolated guinea pig bladder, 5 and also suppressed non-voiding contractions in rats with bladder outlet obstruction. 134,135 There seems to be no published experience of the effects of PDE 4 inhibition in the treatment of OAB/DO. However, previous experience with selective PDE 4 inhibitors used for other indications showed emesis to be a dose-limiting effect.…”

Effects of bladder outlet obstruction on properties of Ca2+-activated K+channels in rat bladder

“…Partial urethral obstruction was produced as previously described (8,20). The bladder and proximal urethra were exposed via a lower abdominal midline incision under isoflurane anesthesia.…”

“…Saline was infused until rhythmic bladder contractions became stable. Parameters listed in Table 1 were determined from cystometrograms as previously described (20). Nonvoiding contractions (NVCs) were defined as bladder contractions without voiding prior to micturition, the amplitudes of which were more than 4 cmH2O.…”