Urinary bladder dysfunction (diabetic cystopathy) is a common complication of diabetes mellitus. Patients have a large capacity bladder with a reduced ability to void. Prior investigations from this laboratory showed that similar changes in in vivo micturition and cystometry occur in both streptozotocin- and spontaneously diabetic BB rats. In addition, structural changes such as hypertrophy, and pharmacological changes 1 to field stimulation and contractile agonists occur in these models. However, there is still little known of the mechanisms responsible for the changes in bladder function associated with diabetes.
The aims of this proposal are to characterize and determine the mechanisms responsible for the changes in bladder function in the spontaneously diabetic BB rat, the animal model which most closely resembles human insulin-dependent diabetes mellitus, and the more severely diabetic model the streptozotocin-diabetic rat, to establish the temporal relationship between the functional and biochemical changes. The questions being asked are: 1) What is the time course for the changes in micturition and urodynamics, 2) What pharmacological and metabolic changes take place, and 3) What is the role of arachidonic acid and the prostaglandins in the development of diabetic cystopathy? A detailed comparison of the relative time courses will help establish causal relationships among the various components. In vivo urinary bladder function will be measured monthly in BB rats using metabolism cages. In vivo cystometry and in vitro contractile and biochemical studies will be done 9, 12, 15, and 18 months after the onset of diabetes in BB rats, and 1, 4, and 8 weeks after induction of diabetes with streptozotocin. Contractile responses of bladder strips and in vitro whole bladders will be measured in response to nerve stimulation and putative neurotransmitters to evaluate changes with time and correlate them with micturition characteristics. Metabolic changes associated with diabetes which may affect bladder function will be determined by determining the ability of the bladder to take up and metabolize glucose, and measuring the intracellular concentrations of glycogen, lactate, ATP, and creatine phosphate. These studies will be correlated with strip studies investigating the effects of decreasing the extracellular glucose concentration on contractile responses to bethanechol. Finally, the responsiveness of bladders to prostaglandins, effects of inhibition of prostaglandin synthesis on contractile responsiveness of bladder strips, endogenous release of prostaglandins, and prostaglandin synthesis from 14C- arachidonic acid will be measured. These studies should improve our knowledge of the changes which occur in the bladder in diabetic cystopathy and the mechanisms responsible for these changes, and may contribute to the development of rational therapeutic approaches for this disorder.
