Yu Y, de Groat W C
Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. yyu+@pitt.edu
Brain Res. 1998 Oct 5;807(1-2):11-8. doi: 10.1016/s0006-8993(98)00707-0.
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.
采用膀胱内压描记法和免疫细胞化学技术，研究了ATP敏感性钾通道开放剂ZD6169和传入神经毒素辣椒素对乙酸（0.25%）刺激膀胱所致膀胱活动亢进及脊髓即刻早期基因表达的影响。大鼠膀胱化学刺激使排尿反射频率增加8倍，并增加了脊髓L6和S1节段背侧连合（DCM）、骶副交感核（SPN）以及内侧和外侧背角（MDH、LDH）神经元中的c-fos表达。用ZD6169（30 nM）预处理1小时可降低乙酸对排尿频率的影响，表现为收缩间期（ICI）增加（增加137±48%，P<0.05）。ZD6169还减少了L6脊髓中Fos阳性神经元的数量，在DCM中减少了62.1±7.1%，在SPN中减少了48.8±7%，在MDH中减少了50±7.3%，在LDH区域减少了38.8±10.5%。在S1脊髓中也观察到类似的减少：DCM中减少65.1±10.8%，SPN中减少53.8±11%，MDH中减少56±10.4%，LDH中减少25.3±18.1%。辣椒素预处理（125 mg/kg，皮下注射，实验前4天）也降低了膀胱活动亢进（ICI增加550%），并减少了乙酸诱导的Fos阳性神经元数量，在脊髓L6节段的DCM中减少78.8±6.3%，在MDH中减少73±7.8%，在LDH中减少59.2±16%，在SPN中减少45.2±17%。这些结果表明，ZD6169可通过抑制已知可调节排尿反射的辣椒素敏感C纤维膀胱传入神经的放电来影响膀胱活动亢进。
