Cold stress-induced bladder overactivity in type 2 diabetic mellitus rats is mitigated by the combination of a M3 -muscarinic antagonist and a β3 -adrenergic agonist.

Abstract

Goto-Kakizaki (GK) rats with type 2 diabetes mellitus respond to low temperature (LT) environments with bladder overactivity, including increased voiding frequency and decreased voiding interval and micturition volume. We determined if bladder overactivity could be inhibited by treatment with the combination of a M3 -muscarinic receptor antagonist and a β3 -adrenergic receptor agonist. Ten-week-old female GK rats were fed a high-fat diet for 4 weeks. Cystometric investigations were conducted at room temperature (RT, 27 ± 2°C). The rats were then intraperitoneally administered the vehicle, the M3 -muscarinic receptor antagonist solifenacin, the β3 -adrenergic agonist mirabegron, or a combination of solifenacin and mirabegron. Ten minutes after the administrations, the rats were transferred to the LT environment (4 ± 2°C), where the cystometric measurements were continued. The expressions of both M3 -muscarinic and β3 -adrenergic receptors were investigated. After transfer from RT to LT, both voiding interval and bladder capacity of the vehicle-, solifenacin-, or mirabegron-treated rats were significantly decreased. However, the combination of solifenacin and mirabegron significantly mitigated the bladder overactivity. While both M3 -muscarinic and β3 -adrenergic receptors were detected, the expression of M3 -muscarinic receptor mRNA was significantly higher than that of β3 -adrenergic receptor mRNA. The cold stress-induced bladder overactivity was not improved by either the M3 -muscarinic receptor antagonist or the β3 -adrenergic receptor agonist alone. However, the combined treatment mitigated the cold stress responses. Combined therapy with M3 -muscarinic antagonists and β3 -adrenergic agonists could reduce side effects and improve the quality of life for diabetic patients with bladder overactivity.