Characterization of neurotransmitter receptors in overactive bladder and drug discovery

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The aim of this study is to characterize alteration of neurotransmitter receptors in overactive bladder and then to develop effective drug therapy. The results obtained here are as follows:1) There were involuntary (spontaneous) contractile activity (in the cystometry) and significant hypertrophy in the bladder of rats received injury of spinal cord.2) The injury of spinal cord in rats brought about a significant increase in the Bmax value for bladder [3H]NMS binding, suggesting up regulation of muscarinic receptor density in the bladder. This increase in the receptor density correlated well with the intensity and frequency of involuntary contractile activity in these rats.3) There were hypertrophy and increase in the muscarinic receptor density in the bladder of rat model with benign prostatic hypertrophy (BPH). These data suggest that there is an increased muscarinic receptor activity in the overactive bladder due to the injury of spinal cord and BPHand that anticholinergic drugs are … More effective to attenuate these symptom in the overactive bladder.4) Significant amount of specific [3H]αβ-MeATP binding was detected in the homogenates of rat bladder. Specific [3H]-ATP binding in the bladder was inhibited by αβ-MeATP, βγ-MeATP, MRS2273, PPADS and suramine in the concentration dependent manner. The binding affinity was greater in, the following order: αβ-MeATP>βγ-MeATP>suramine>PPADS>MRS2273.These data suggest that ATP receptor (P2X subtype) is present in the rat bladder and that this receptor is a target molecule for the drug therapy.5) Tolterodine (relatively novel anticholinergic agent) has been shown to bind significantly to the mouse bladder muscarinic receptors by oral administration, and the mode of binding is more slow and longer-lasting than that of oxybutynin, a commonly used anticholinergic agent to treat overactive bladder. The inhibition of pilocarpine evoked salivation by oral administration of tolterodine was significantly weaker than that of oxybutynin.These data indicate that tolterodine may be more advantageous than oxybutynin in terms of low incidence of dry mouth in patients with overactive bladder. Less