Urinary bladder dysfunction is a common complication of diabetes mellitus, presenting as a large capacity bladder with a reduced ability to void.
The aim of this project is to characterize the mechanisms responsible for the changes in bladder function caused by diabetes. The spontaneously diabetic BB rat, the animal model which most closely resembles human insulin-dependent diabetes mellitus, will be used. Rats will be studied 30 and 120 days after the onset of diabetes. Preliminary results indicate that bladder dysfunction is present in the BB rat 60 days after the onset of diabetes. An in-vivo cystometrogram method will be used to compare the nature of rat bladder dysfunction with that in human diabetics. Pharmacological organ-bath studies measuring contractile responses of bladder body and base strips to nerve stimulation and to agonists will be carried out. The transmitters responsible for the neurogenic response will be characterized using specific antagonists. Agonists and antagonists which improve bladder strip contractile function in-vitro will be tested in-vivo to determine whether they also improve whole bladder cystometrogram responses. Calcium channel antagonists will be used to determine whether the dependence of bladder contraction on extracellular calcium is similar in bladders from control and BB rats. The involvement of receptors and intracellular events in diabetic bladder dysfunction will be examined. Release of labelled norepinephrine from the bladder after nerve stimulation will be measured to determine the efficacy of norepinephrine release mechanisms. In addition, endogenous norepinephrine levels will be measured to give an estimate of sympathetic neuronal activity in the bladder. Labelled specific muscarinic and sympathetic antagonists will be used to determine sympathetic and muscarinic receptor numbers and affinities in bladders of control and BB rats. Finally, the role of myo-inositol and inositol phosphates, lipids which are involved in receptor coupling and calcium influx, and which are decreased in diabetes, will be studied. These experiments should improve our knowledge of the changes which occur in diabetic cystopathy, and of the mechanisms responsible for these changes.
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