The functional response of the urinary bladder is only partially due to cholinergic innervation since atropine does not completely block neuronally induced contractions. Evidence accumulated over the past few decades indicates that this atropine resistant contraction may be mediated by ATP or a related purine compound. The goals of the studies herein proposed are: (1) to identify a post synaptic receptor for this purinergic system using radioligand binding methodologies. This first goal will be accomplished by characterizing the binding of 3H-beta,gamma methylene ATP (APPCP) to bladder membranes. (2) To determine whether this receptor is responsible for the atropine resistant contractile response. Three means of accomplishing this goal will be used: (a) comparing the Ki for physiological antagonists obtained by Schild analysis with Ki for antagonists obtained by radioligand binding methodology, (b) comparing radioligand binding data from bladder dome (which does contract in response to purinergic agonists) with binding data from the bladder base (which does not contract in response to purinegic agonists). (c) using arylazido amino propionyl ATP to covalently bind the purinergic receptor and thereby prevent both contractile response to purinergic agonists and binding of radioligands to the receptor. (3) To determine the role which this purinergic system plays in urologic function. An in-vitro whole bladder model developed in our laboratories will be used to accomplish this third goal. It has been estimated that, in the human bladder, this non-cholinergic (possibly purinergic) system is responsible for 50% of the contractile response. Accomplishing the above described goals will lead to a better understanding of urinary bladder function and possibly form the foundation of a new class of therapeutic agents for the treatment of urinary bladder disfunction.
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