Effect of the alpha2-adrenoceptor agonist PGE6201204 on micturition parameters in conscious spontaneously hypertensive rats

Sheridan Piper-Brown, Tony Kirkup & Gordon McMurray (Introduced by Wesley Miner). Discovery Biology, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ.

Overactive bladder (OAB) is a widespread urological condition with bothersome symptoms such as urgency, frequency, bladder hyperactivity and associated episodes of incontinence. Potential treatments for OAB aim to increase bladder capacity whilst reducing bothersome symptoms, in particular urgency. a 2 -adrenoceptor agonists have been shown, in vitro, to reduce neurally evoked bladder contractions via the α2A -adrenoceptor (Piper-Brown and McMurray, 2005), which may lead to a reduction in bladder activity in vivo. As such this study investigated the effects of PGE6201204, a selective α2-adrenoceptor full agonist, on micturition parameters in conscious spontaneously hypertensive rats (SHR). SHRs have been shown to exhibit reduced bladder capacity and voided volume, increased urinary frequency and increased occurrence of non-voiding contractions in comparison to their genetic control strain the Wistar Kyoto (WKY) rat, features reminiscent of many of the symptoms in OAB. All experiments were carried out in compliance with UK legislation.

A total of 24 female animals were used, divided into 3 groups of 8 rats, which were numbered via tail marking. A cross over dosing design was incorporated such that all rats received vehicle (saline) and a single dose of drug (PGE-6201204 at either 3, 10 or 30μg/kg) sub-cutaneously (s.c.) in a randomised manner with at least 3 days allowed between treatments for each animal. On each day of the study rats were removed from their cage and dosed s.c. in the rear right flank. Subsequently rats were placed in individual metabols (metabolic cage) each over a urine capture system for 3 to 3.5 hours. On every day of the study each rat had their individual micturition parameters defined in terms of total number of voids, total volume voided (cumulative volume throughout 3hr period) and average volume/void (calculated as the total volume voided/total number of voids). Subsequently individual analysis was combined for each of the treatment groups and their vehicle controls. Statistical significance for all parameters was assessed using a two-way paired Student’s t-test. Statistical comparisons were only carried out in regard to individual treatment groups such that animals were compared to their own vehicle control data. Differences were considered significant at p<0.05.

A dose-dependent increase in volume per void, voiding frequency and total volume voided was observed with s.c. administration of PGE-6201204. Volume per void increased by 18.3% (95% CI –17.4, 54.1), 55.7% (95% CI 7.15, 104.3) and 66.9% (95% CI 39.7, 92.1) at 3, 10 and 30μg/kg respectively. At 10 and 30μg/kg this change was highly significant (p<0.05). The increase in frequency was 92.1% and 112.9%, with an increase in total volume of 197.9% and 253.3% at the 10 and 30μg/kg doses respectively. These values were highly significant p<0.05.

This study demonstrates an efficacious effect of PGE6201204 on bladder capacity in conscious SHRs, however this is accompanied by a significant increase in diuresis.

Piper-Brown S and McMurray G http://www.pa2online.org/abstracts/Vol3Issue4abst030P.pdf.