Effects of ZD6169, a K(ATP) channel opener, on the micturition reflex in the rat.
The effects of ZD6169, a new ATP-sensitive potassium channel opener, on reflex urinary bladder activity were evaluated in urethane-anesthetized female Wistar rats. Continuous transvesical slow infusion cystometrograms (0.04 ml/min) were performed in untreated, capsaicin-pretreated (125 mg/kg s.c., 4 days before experiments) and capsaicin vehicle-pretreated rats. Intravesical infusion of ZD6169 in concentrations of 6, 15, 30, and 300 nM for 2 h at each concentration increased the intercontraction interval and pressure threshold for voiding in a concentration-dependent manner in untreated and vehicle-pretreated rats but not in capsaicin-pretreated animals. The effects appeared within 30 min after administration. ZD6169 did not alter baseline bladder pressure, duration of contractions, or the peak pressure during voiding. Glibenclamide (20 mg/kg i.v.) reversed the effects of ZD6169 (30 nM). During transvesical cystometrograms performed at a fast rate (0.21 ml/min), ZD6169 in concentrations between 6 and 300 nM did not alter the intercontraction interval or pressure threshold for voiding. ZD6169 produced smaller and more variable effects during slow transurethral cystometrograms. Capsaicin, a C-fiber afferent neurotoxin, administered s.c. 4 days before the experiment, produced similar changes and also eliminated the effect of ZD6169. These data suggest that ZD6169 raises the threshold for activation of C-fiber mechanoreceptors in the bladder wall and thereby increases the bladder volume for inducing reflex voiding.