The long range goals of this project are to define the role of the different muscarinic receptor subtypes in normal bladder function and to determine the changes that occur with bladder dysfunction. The most significant accomplishment of our previous studies is the discovery that the muscarinic receptor subtype mediating bladder contraction changes from M3 dominance in normal bladders to M2 in denervated and spinal injured rat bladders. Results obtained from the limited human bladder tissue available to us during this period suggests that this may be true for human bladder as well. This finding, if confirmed in a large series of human bladder specimens, has important implications for design of muscarinic agents for urologic use and may help explain the clinical efficacy of the M2-M3 selective antimuscarinic drug tolterodine. This is based on the recently proposed concept that bladder overactivity results from varying degrees of functional or actual motoneuron denervation of the detrusor.
The specific aims of this proposal are: l. To characterize the mechanisms involved in transduction of the contractile effect of M2 and M3 muscarinic receptor stimulation in normal bladder. 2. To characterize the changes in mechanisms involved in contractile signal transduction following bladder denervation and spinal injury. 3. To characterize the changes in M2 M3 receptor phosphorylation that may accompany receptor desensitization and receptor up and down regulation.
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