Effects of ZD6169, a K ATP channel opener, on neurally-mediated plasma extravasation in the rat urinary bladder induced by chemical or electrical stimulation of nerves.
The effects of oral administration of ZD6169, a potassium channel opener, on neurally mediated plasma extravasation in the urinary bladder and urethra were examined in urethane-anesthetized rats. Plasma extravasation was evaluated by measuring the tissue concentration of Evans blue, administered intravenously (50 mg/kg) 15 min prior to removal of tissues. Plasma extravasation was induced by three different stimuli: intravesical administration of either 0.25% acetic acid or 100 microM capsaicin or electrical stimulation of the pelvic nerve on one side (50 V, 10 s trains, 30 Hz intra-train frequency at 1 min intervals for 40 min). ZD6169 (5 mg/kg), administered orally 5 h prior to stimulation, significantly reduced the capsaicin-induced (50% decrease, p<0.05) or the electrical stimulation-induced (58% decrease, p<0.05) plasma extravasation in the bladder, but did not prevent the plasma extravasation in the bladder or urethra induced by intravesical infusion of 0.25% acetic acid. Administration of a K(ATP) channel blocker, glibenclamide (20 mg/kg, iv) 45 min prior to ZD6169 administration blocked the effects of ZD6169 on the electrical stimulation-induced plasma extravasation in the bladder and reduced the effects of ZD6169 on capsaicin-induced plasma extravasation. These findings indicate that ZD6169 (and/or a metabolite) can reduce neurogenic plasma extravasation in the bladder and are consistent with other studies indicating that ZD6169 can activate K(ATP) channels in C-fiber bladder afferents and suppress afferent activity.
Yu
Yongbei
Y
Department of Pharmacology, School of Medicine, University of Pittsburgh, 13th Fl Biomed Sci. Tower, Pittsburgh, PA 15261, USA. yyu+@pitt.edu
Fraser
Mathew O
MO
de Groat
William C
WC
D019342:Acetic Acid / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods*; D005070:Evans Blue / Q000378:metabolism; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D008565:Membrane Proteins / Q000819:agonists*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D014521:Urethra / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
D000577:Amides; D000889:Anti-Arrhythmia Agents; D001577:Benzophenones; D001798:Blood Proteins; D008565:Membrane Proteins; D015221:Potassium Channels; C095007:Zeneca ZD 6169; C117780:mitochondrial K(ATP) channel; D005070:Evans Blue; D019342:Acetic Acid; D002211:Capsaicin; D005905:Glyburide