Vesical dysfunction is a recognized complication of diabetes mellitus and is attributed in part to autonomic neuropathy. The induction of experimental diabetes in rats by diabetogenic agents provides an appropriate model for studying various histological, biochemical and pharmacological alterations that occur in the diabetic bladder. Utilizing streptozotocin (STZ)-induced diabetic rats, we have shown an up-regulation of beta adrenergic and muscarinic cholinergic receptors in 8-week diabetic bladder dome. The increase in the density of muscarinic receptors correlates directly with an increased agonist-induced contractile response of isolated muscle strips. We also have shown an up-regulation of muscarinic receptors, but not beta receptors, in diuresis-induced hypertrophied bladders obtained from rats receiving 5% sucrose in their drinking water. These data provide the rationale for a working hypothesis that bladder dysfunction in diabetes mellitus is in part the manifestation of the alterations occurring in the physical properties of bladder smooth muscle. The main objectives of this proposal are to determine how and why diabetes mellitus alters the function of bladder smooth muscle and to determine to what extent these alterations can be prevented, delayed, or corrected. To achieve this goal, changes in the diabetic bladder will be studied at several levels: 1) autonomic receptors, 2) receptor-effector regulatory proteins and respective enzymes, and 3) contractile functional response. It is planned to maintain the following groups of diabetic, diuretic, and age-matched control rats for a period of 2 weeks to 1 year: STZ-induced diabetics;l sugar-induced diuretics; insulin-, myoinositol-, sodium vanadate- and aminoguanidine-treated diabetics; and their appropriate control groups. Each group will be studied for a) identification and characterization of adrenergic and muscarinic cholinergic receptors in membrane particulates using radioligand binding assays, b) autoradiographic identification and localization of these receptors in tissue sections, c) characterization of guanine nucleotide-binding proteins (G-proteins) and respective enzyme processes, and d) determination of nerve stimulation and agonist-induced contractile responses of isolated muscle strips. The correlation between the biochemical and functional studies will hopefully provide information regarding mechanisms involved in the development of the diabetic bladder, and a rationale for the pharmacologic management of this pathologic condition.
