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.
Yu
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Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. yyu+@pitt.edu
de Groat
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WC
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008465:Mechanoreceptors / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014554:Urination / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects
D000577:Amides; D001577:Benzophenones; D007004:Hypoglycemic Agents; D015221:Potassium Channels; C095007:Zeneca ZD 6169; D000255:Adenosine Triphosphate; D002211:Capsaicin; D005905:Glyburide