title: Role of alpha2-adrenoceptors and glutamate mechanisms in the external urethral sphincter continence reflex in rats.
abstract: OBJECTIVE
  We investigated the role of alpha(2)-adrenoceptors and glutamate mechanisms in the urethral continence reflex in response to abdominal pressure increases.
  
  
  METHODS
  Under urethane anesthesia external urethral sphincter electromyogram activity was evaluated in spinal cord transected (T8-T9) female rats during lower abdominal wall compression before and after intravenous application of test drugs. The effects of the N-methyl-D-aspartate glutamate receptor antagonist MK-801 (Sigma) or the alpha(2)-adrenoceptor agonist medetomidine (Tocris Cookson, Ellisville, Missouri) (each 0.03, 0.3 and 3 mg/kg intravenously) on external urethral sphincter activity were examined. A 0.3 mg/kg intravenous dose of the alpha(2)-adrenoceptor antagonist idazoxan (Sigma) was then administered before or after the application of 1 mg/kg MK-801 intravenously. In addition, 0.3 mg/kg idazoxan were administered intravenously following the application of 1 mg/kg of the serotonin/norepinephrine reuptake inhibitor duloxetine (Kemprotec, Middlesbrough, United Kingdom) intravenously.
  
  
  RESULTS
  MK-801 and medetomidine dose dependently decreased external urethral sphincter activity. Idazoxan significantly increased external urethral sphincter activity by 64% but the increase in activity after idazoxan was abolished by MK-801. On the other hand, idazoxan did not reverse the inhibitory effects of MK-801. In addition, idazoxan significantly potentiated the duloxetine effects on external urethral sphincter activity by 120%.
  
  
  CONCLUSIONS
  These results indicate that 1) glutamate is a major excitatory neurotransmitter in the urethral continence reflex response to abdominal pressure increases, 2) alpha(2)-adrenoceptor activation suppresses external urethral sphincter activity, probably via presynaptic inhibition of glutamate release and 3) the effects of serotonin/norepinephrine reuptake inhibitors are enhanced by alpha(2)-adrenoceptor inhibition. Therefore, alpha(2)-adrenoceptor antagonists could be beneficial for treating stress urinary incontinence.
authors.affiliation: Department of Urology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Furuta
authors.forename: Koji
authors.initials: K
authors.lastname: Asano
authors.forename: Shin
authors.initials: S
authors.lastname: Egawa
authors.forename: William C
authors.initials: WC
authors.lastname: de Groat
authors.forename: Michael B
authors.initials: MB
authors.lastname: Chancellor
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012018:Reflex / Q000502:physiology*; D014521:Urethra / Q000502:physiology*
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D018698:Glutamic Acid