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 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. (C) 1998 Elsevier Science B.V. All rights reserved.