α2-Adrenoceptor as a New Target for Stress Urinary Incontinence

Objectives: We examined glutamate and/or alpha(2)-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 alpha(2)-AR agonist, for EUS activity were examined. Idazoxan (0.3 mg/kg i.v.), an alpha(2)-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. Conclusion: These results indicate that glutamate is a major excitatory neurotransmitter in the urethral continence reflex response to abdominal pressure increases and that alpha(2)-AR activation suppresses EUS activity, most likely via the presynaptic inhibition of glutamate release. Therefore, the alpha(2)-AR antagonist would represent a new therapeutic target for the treatment of stress urinary incontinence.