Impaired M3 and Enhanced M2 Muscarinic Receptor Contractile Function in a Streptozotocin Model of Mouse Diabetic Urinary Bladder

Authors

K. J. Pak, University of California, Irvine
Rennolds S. Ostrom, Chapman UniversityFollow
M. Matsui, Tokyo-Nishi Tokushukai Hospital
F. J. Ehlert, University of California, Irvine

Document Type

Article

Publication Date

2010

Abstract

We investigated the contractile roles of M2 and M3 muscarinic receptors in urinary bladder from streptozotocin-treated mice. Wild-type and M2 muscarinic receptor knockout (M2 KO) mice were given a single injection of vehicle or streptozotocin (125 mg kg−1) 2–24 weeks prior to bladder assays. The effect of forskolin on contractions elicited to the muscarinic agonist, oxotremorine-M, was measured in isolated urinary bladder (intact or denuded of urothelium). Denuded urinary bladder from vehicle-treated wild-type and M2 KO mice exhibited similar contractile responses to oxotremorine-M, when contraction was normalized relative to that elicited by KCl (50 mM). Eight to 9 weeks after streptozotocin treatment, the EC50 value of oxotremorine-M increased 3.1-fold in urinary bladder from the M2 KO mouse (N = 5) compared to wild type (N = 6; P < 0.001). Analogous changes were observed in intact bladder. In denuded urinary bladder from vehicle-treated mice, forskolin (5 µM) caused a much greater inhibition of contraction in M2 KO bladder compared to wild type. Following streptozotocin treatment, this forskolin effect increased 1.6-fold (P = 0.032). At the 20- to 24-week time point, the forskolin effect increased 1.7-fold for denuded as well as intact bladders (P = 0.036, 0.01, respectively). Although streptozotocin treatment inhibits M3 receptor-mediated contraction in denuded urinary bladder, muscarinic contractile function is maintained in wild-type bladder by enhanced M2 contractile function. M2 receptor activation opposes forskolin-induced relaxation of the urinary bladder, and this M2 function is enhanced following streptozotocin treatment.

Comments

This article was originally published in Naunyn-Schmiedeberg's Archives of Pharmacology, volume 381, issue 5, in 2010. DOI: 10.1007/s00210-010-0509-6

Recommended Citation

Kirk J. Pak, Rennolds S Ostrom, Minoru Matsui and Frederick J Ehlert. Impaired M3 and enhanced M2 muscarinic receptor contractile function in a streptozotocin model of mouse diabetic urinary bladder. Naunyn-Schmiedebergs Arch Pharmacol, 381(5):441-54, 2010.

Copyright

The authors