Despite the significant clinical problems of bladder dysfunction, specifically affecting the individual's quality of life, our understanding of this disease is limited. The main problem relates to the lack of clinically relevant models. The paper by Shimizu et al. describes the development of a neurogenic bladder model in the rat by an electrolytic unilateral lesion of the right basal forebrain. This model mimics the clinical situation of increased voiding frequency and decreased micturition threshold pressure. The group also uses this model to test the effects of AH-9700, a potent sigma receptor-agonist, with some success. The overall develop of clinically relevant models has important implications in future drug development and testing.
To investigate the changes in bladder function in rats with an electrolytic lesion of the right basal forebrain (RBF) and to determine the effects of AH-9700, a novel sigma receptor ligand, on cystometry in RBF-lesioned rats.
MATERIALS AND METHODS
A lesion was made electrolytically in the RBF of male Wistar rats. At 7 or 8 days after the lesion or sham surgery, continuous cystometry was performed in awake rats. In addition, contractile responses to electrical field stimulation or carbachol were measured in isolated bladder strips, as were the forebrain contents of acetylcholine, monoamine neurotransmitters and their metabolites.
RBF-lesioned rats showed a remarkable increase in voiding frequency, with a decrease in voiding threshold pressure but no change in voiding pressure, compared with sham-operated rats. However, contractile responses in bladder strips isolated from RBF-lesioned rats were no different from those in strips isolated from sham-operated rats. In RBF-lesioned rats, the contents of acetylcholine, dopamine, 4-dihidroxyphenylacetic acid and homovanillic acid were significantly decreased in the right forebrain. AH-9700 dose-dependently decreased the voiding frequency and increased the threshold pressure in RBF-lesioned rats. Anti-muscarinic agents (oxybutynin and propiverine) also decreased the voiding frequency, but their effects were less potent than that of AH-9700.
The RBF-lesioned rat may be a useful model for the neurogenic bladder of supraspinal origin. Moreover, AH-9700 effectively improves bladder dysfunction in this model.