α2‐Adrenoceptor as a New Target for Stress Urinary Incontinence

Abstract

Objectives: We examined glutamate and/or α2‐adrenoceptor (AR) mechanisms in the control of external urethral sphincter (EUS) activity in response to stress conditions.Methods: Under urethane anesthesia, EUS electromyogram activity was evaluated in spinal cord‐transected (T8‐9) female rats during lower abdominal wall compression before and after the intravenous (i.v.) application of test drugs. The effects of MK‐801 (0.03, 0.3, and 3 mg/kg i.v.), an N‐methyl‐D‐aspartate glutamate receptor antagonist, or medetomidine (0.03, 0.3, and 3 mg/kg i.v.), an α2‐AR agonist, for EUS activity were examined. Idazoxan (0.3 mg/kg i.v.), an α2‐AR antagonist, was then administered before or after the application of MK‐801 (1 mg/kg i.v.).Results: Both MK‐801 and medetomidine dose‐dependently decreased EUS activity during abdominal compression. Idazoxan significantly increased EUS activity by 64%, but EUS activity during abdominal compression, which increased after idazoxan, was abolished by MK‐801. However, idazoxan did not reverse the inhibitory effects of MK‐801 on EUS activity during abdominal compression.Conclusions: These results indicate that glutamate is a major excitatory neurotransmitter in the urethral continence reflex response to abdominal pressure increases and that α2‐AR activation suppresses EUS activity, most likely via the presynaptic inhibition of glutamate release. Therefore, the α2‐AR antagonist would represent a new therapeutic target for the treatment of stress urinary incontinence.