Effects of the K+ channel opener, ZD6169, on volume and PGE(2)-stimulated bladder activity in conscious rats

Purpose: To investigate the effects of the new K-ATP channel opener, ZD6169, shown to have an in vivo selectivity for the bladder, on bladder activity in rats. Materials and Methods: ZD6169 was given intra-arterially (i.a., 0.1 and 1 mg./kg.) or orally (3 mg./kg.) to conscious Sprague-Dawley rats undergoing continuous cystometry. Investigations were also performed before and after stimulation of bladder activity by intravesical prostaglandin (PG) E-2. Results: Intra-arterial ZD6169 increased residual volume, but caused no changes in other cystometric parameters. In rats receiving oral ZD6169, cystometric parameters were compared (every hour up to five hours) to those recorded in rats receiving oral vehicle. No differences were found, except in threshold pressure, which was significantly increased. Intravesical PGE(2) 20 mu U M increased micturition and basal pressures, and decreased bladder capacity and micturition volume. ZD6169 1 mg./kg., given i.a., reduced or completely prevented the activity induced by intravesical PGE(2). Three hours after orally administered ZD6169 (3 mg./kg.), intravesical PGE(2) 20 mu M had no effect. Three hours after oral administration of vehicle, the effects of PGE(2) were attenuated, but still statistically significant. Conclusions: ZD6169, given i.a. or orally, increased threshold pressure, but had otherwise little effect on volume-induced micturition. However, the drug markedly reduced or prevented PGE(2)-induced bladder activity when given i.a.; it was also effective when given orally. If ZD6169 has inhibiting effects on bladder contraction in man without any cardiovascular actions, the drug may represent a novel, promising way of treating bladder overactivity.