Effects of ZD6169, a K ATP channel opener, on bladder hyperactivity and spinal c- fos expression evoked by bladder irritation in rats

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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 L 6 and S 1 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 L 6 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 S 1 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 L 6 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.