The M2-muscarinic receptor inhibits the development of streptozotocin-induced neuropathy in mouse urinary bladder

• Published in: The Journal of pharmacology and experimental therapeutics 2010-10, Vol.335 (1), p.239-248
• Main Authors: Pak, K J, Ostrom, R S, Matsui, M, Ehlert, F J
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Adrenergic beta-Agonists - pharmacology; Algorithms; Animals; Antibiotics, Antineoplastic; Blood Glucose - metabolism; Body Weight - drug effects; Electric Stimulation; Endocrine and Diabetes; Hyperglycemia - chemically induced; Hyperglycemia - pathology; In Vitro Techniques; Isoproterenol - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscarinic Antagonists - pharmacology; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth - drug effects; Organ Size - drug effects; Receptor, Muscarinic M2 - drug effects; Receptor, Muscarinic M2 - genetics; Streptozocin; Urinary Bladder, Neurogenic - chemically induced; Urinary Bladder, Neurogenic - prevention & control
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.169995

We investigate the role of M(2)-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 M(2)-muscarinic receptor knockout (M(2) 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 M(2) 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 M(2) 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. M(2) 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 M(2) receptors oppose urinary bladder distension in wild-type bladder and inhibit streptozotocin-induced neuropathy.