Muscarinic receptor activation in the lumbosacral spinal cord ameliorates bladder irritation in rat cystitis models.
OBJECTIVE
To investigate whether activation of spinal cholinergic pathways affects bladder activity in rats with chemical cystitis induced by acetic acid (AA) and cyclophosphamide (CYP).


METHODS
The effects of intrathecal (i.t.) application of neostigmine as an acetylcholine esterase (AChE) inhibitor, oxotremorine-M (OXO-M) as a muscarinic ACh receptor (mAChR) agonist or epibatidine as a nicotinic AChR (nACHR) agonist with or without atropine as a mAChR antagonist or mecamylamine (MEC) as a nAChR antagonist at the level of L6-S1 spinal cord on C-fibre mediated bladder irritation were examined by using continuous-infusion cystometry (0.1 mL/min) in urethane-anaesthetized female Spraque-Dawley rats. Bladder irritation was induced by intravesical AA (0.25%) or pretreatment with intraperitoneal injection of CYP (150 mg/kg) 24 h before cystometry. In control rats during intravesical saline, the effects of above drugs on the bladder activity were also examined.


RESULTS
The intercontraction intervals (ICI) in AA- and CYP-treated rats were significantly shorter than those in control rats. Neostigmine (i.t.) significantly increased ICI dose-dependently without changing maximum voiding pressure in all groups. The mean (sem) maximal percentage increases in ICI after i.t. neostigmine as compared with the pretreatment value in control, AA- and CYP-treated rats were 93.2 (18.5)%, 117.5 (20.2)% and 200.7 (19.6)%, respectively. The percentage increases of ICI in the CYP-treated group were significantly (P < 0.05) higher than those in the AA-treated or control groups. In all groups, pretreatment with atropine, but not MEC, almost completely antagonized the inhibitory effects of neostigmine. OXO-M produced almost the same effects as that of neostigmine in all groups. Conversely, i.t. epibatidine decreased the ICI in all groups and these excitatory effects were completely antagonized by pretreatment with MEC and significantly inhibited by pretreatment with MK-801(noncompetitive n-methyl-d-aspartate receptor antagonist).


CONCLUSIONS
These results indicate that accumulation of ACh by AChE inhibition in the spinal cord can ameliorate frequent urination in chemical cystitis via mAChRs, but not nAChRs.
Masuda
Hitoshi
H
Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan. hi-masu.uro@tmd.ac.jp
Ichiyanagi
Nobutaka
N
Yokoyama
Minato
M
Sakai
Yasuyuki
Y
Kihara
Kazunori
K
Chancellor
Michel B
MB
de Groat
William C
WC
Yoshimura
Naoki
N
D000818:Animals; D003556:Cystitis / Q000188:drug therapy*; D005260:Female; D008159:Lumbar Vertebrae; D018721:Muscarinic Agonists / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012447:Sacrum
D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D011976:Receptors, Muscarinic