Pharmacological Properties, Functional Alterations and Gene Expression of Muscarinic Receptors in Young and Old Type 2 Goto-Kakizaki Diabetic Rat Bladders

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Purpose:We investigated pharmacological properties, functional alterations and gene expression of the muscarinic receptor system in young and old Goto-Kakizaki rat bladders.Materials and Methods:Male 12 and 70-week-old Goto-Kakizaki rats and age matched male Wistar rats were used in this study. Bladder function was estimated by voiding behavior, cystometric and functional studies using KCl, carbachol and various concentrations of subtype selective muscarinic antagonists, ie pirenzepine, methoctramine, 4-DAMP (Sigma®) and atropine (Wako Pure Chemical Industries, Osaka, Japan). The participation levels of M2 and M3 receptor mRNA in the bladder were investigated by real-time polymerase chain reaction.Results:In voiding behavior studies there were no significant differences in urine output, although an age related decrease in micturition frequency and an age related increase in single voided volume were observed in Goto-Kakizaki and Wistar rats. In cystometric studies there were no significant differences in maximum detrusor pressure or bladder capacity, although residual urine volume was significantly increased in 70-week-old Goto-Kakizaki rats. In functional studies carbachol induced detrusor contractility was significantly increased in Goto-Kakizaki rats in each age group. Estimated pA2 values for atropine, pirenzepine, methoctramine and 4-DAMP (Sigma) indicated that the carbachol induced contractile response was mediated through the M3 receptor subtype in all groups. Furthermore, muscarinic M2 and M3 receptor mRNA was significantly up regulated in 70-week-old Goto-Kakizaki rat bladders.Conclusions:Our data indicate that noninsulin dependent diabetes induces alterations in the muscarinic receptor system, which may contribute to the development of diabetic cystopathy.

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