Effects of ZD6169, a KATP channel opener, on bladder hyperactivity and spinal c-fos expression evoked by bladder irritation in rats.
Cystometrographic recording and immunocytochemical techniques were used to examine the effects of ZD6169, an ATP-sensitive K+-channel opener, and capsaicin, an afferent neurotoxin, on urinary bladder hyperactivity and immediate early gene expression in the spinal cord induced by acetic acid (0.25%) irritation of the bladder. Chemical irritation of the bladder of the rat increased the frequency of voiding reflexes by 8 fold and increased c-fos expression in neurons in the dorsal commissure (DCM), sacral parasympathetic nucleus (SPN) as well as the medial and lateral dorsal horn (MDH, LDH) of L6 and S1 segments of the spinal cord. Pretreatment with ZD6169 (30 nM) for 1 h reduced the effect of acetic acid on voiding frequency as reflected by an increase in the intercontraction interval (ICI, 137+/-48% increase, P<0.05). ZD6169 also decreased the number of Fos positive neurons in the L6 spinal cord, in the DCM (62.1+/-7.1% decrease), SPN (48.8+/-7%), MDH (50+/-7.3%) and LDH regions (38. 8+/-10.5%). Similar reductions were noted in the S1 spinal cord: 65. 1+/-10.8% in DCM, 53.8+/-11% in SPN, 56+/-10.4% in MDH and 25.3+/-18. 1% in LDH. Capsaicin pretreatment (125 mg/kg, s.c., 4 days prior to the experiments) also reduced bladder hyperactivity (550% increase in ICI) and decreased the numbers of acetic acid-induced Fos positive neurons 78.8+/-6.3% in DCM, 73+/-7.8% in MDH, 59.2+/-16% in LDH and 45.2+/-17% in SPN of L6 segment of the spinal cord. These results suggest that ZD6169 can influence bladder hyperactivity by suppressing the firing of capsaicin-sensitive C-fiber bladder afferents which are known to modulate the micturition reflex.
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Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. yyu+@pitt.edu
de Groat
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005260:Female; D015640:Ion Channel Gating; D007509:Irritants / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009498:Neurotoxins / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects*
D000577:Amides; D001577:Benzophenones; D007509:Irritants; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D015221:Potassium Channels; D016760:Proto-Oncogene Proteins c-fos; C095007:Zeneca ZD 6169; D000255:Adenosine Triphosphate; D002211:Capsaicin