Bladder dysfunction is a common complication of diabetes mellitus and is manifest at an early stage by deficient bladder sensation that can result in increased bladder capacity and size, and often progresses to urinary retention. Although these disturbances in part are attributed to diabetes- induced autonomic neuropathy, the mechanism responsible for the bladder dysfunction remains unclear. The unifying hypothesis of this proposal is that diabetes causes alterations at the receptor-effector level in the urinary tract and that these alterations are region and receptor specific. Furthermore, changes in the hormonal balance as well as in the physical properties of the urinary tract are important in the development of vesical dysfunction in diabetes mellitus. We have shown that: a) both diabetes and sucrose-induced diuresis cause an upregulation of muscarinic receptors and an increase in the contractile response of the bladder dome to muscarinic agonists; b) early insulin treatment prevents but late insulin treatment only partially reverses the diabetes-induced upregulation of bladder dome muscarinic receptors and bladder hypertrophy, whereas the removal of sucrose from the drinking water of diuretic rats normalizes both of these alterations; c) there is an alteration in muscarinic receptor-G protein coupling in the bladder dome of both diabetic and diuretic rats; d) diabetes, but not sucrose- induced diuresis, causes an upregulation in detrusor beta adrenergic and endothelin receptors; and e) there is an enhancement of muscarinic receptor-coupled phosphatidyl inositol hydrolysis in the diabetic rat bladder. To test our hypothesis we will determine the differential effects of chemically-induced diabetes and sugar-induced diuresis on the biochemical and functional characteristics of autonomic, endothelin and calcium antagonist receptors in the renal pelvis, ureter, bladder dome, bladder base and urethra of experimentally-induced diabetic and diuretic rat and rabbit models. It is planned to: 1) identify and characterize changes in the subtype specificity of these receptors, and to determine the tissue(s) and cell type(s) in which these receptors and their mRNAs are located; 2) determine the impact of the receptor changes on the physiological contractile functions of urinary tract smooth muscle; 3) prevent, ameliorate or reverse with pharmacological interventions the diabetes-and/or diuresis- induced receptor alterations, and to assess the impact of bladder hypertrophy on the development of diabetic bladder dysfunction and/or neuropathy. These studies will increase our understanding of the mechanisms involved in the development of diabetes-induced vesical dysfunction and provide a rationale for its pharmacological management.
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