Abstract
We investigate the role of M2-muscarinic receptors in maintaining neurogenic bladder contraction during hyperglycemia. Mice were injected with a single dose of streptozotocin (125 mg/kg), and neurogenic contraction of urinary bladder from wild type and M2-muscarinic receptor knockout (M2 KO) mice was measured at 8 to 24 weeks after treatment. In wild-type bladder lacking urothelium, the summation of the cholinergic (64%) and purinergic (56%) components of the electrical-field-stimulated response exceeded 100%, indicating a reserve capacity. Although the cholinergic component was slightly less in the M2 KO mouse, the total electrical-field-stimulated contraction was the same as wild type. The cholinergic and purinergic components of contraction in wild-type bladder were minimally affected by streptozotocin treatment. In M2 KO bladder, streptozotocin treatment reduced both the cholinergic (after 8–9 and 20–24 weeks) and purinergic (after 20–24 weeks only) components. The loss of function was approximately 50 to 70%. Similar results were observed in bladder with intact urothelium. M2 KO bladder was more sensitive to the relaxant effect of isoproterenol compared with wild type, and this difference significantly increased at the early and late time points after streptozotocin treatment. In the presence of urothelium, however, this difference in isoproterenol sensitivity was smaller with streptozotocin treatment, but this trend reversed over time. Our results show that M2 receptors oppose urinary bladder distension in wild-type bladder and inhibit streptozotocin-induced neuropathy.
Footnotes
This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant F30-DK081289]; the University of Tennessee Federal Flow-Through Funds from the National Institutes of Health National Heart, Lung and Blood Institute [Grant UTN-37775]; the National Institutes of Health National Institutes of General Medical Sciences [Grant R01-GM069829]; Arnold and Mabel Beckman Foundation and Achievement Rewards for College Scientists Foundation; and the University of California Irvine Medical Scientist Training Program.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.169995.
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ABBREVIATIONS:
- EFS
- electrical-field-stimulated
- STZ
- streptozotocin
- KO
- knockout
- mATP
- α,β-methylene ATP
- NMS
- N-methylscopolamine
- TTX
- tetrodotoxin.
- Received May 4, 2010.
- Accepted July 8, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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