Influence of glutamate receptor antagonists on micturition in rats with spinal cord injury.
This study was undertaken to determine if an AMPA (LY215490) or an NMDA (MK-801) glutamatergic receptor antagonist can reduce urinary tract dysfunctions related to detrusor hyperreflexia and detrusor-sphincter dyssynergia in awake, spinal cord-injured (SCI) rats. Experiments were performed on female Sprague-Dawley rats in which the spinal cord was completely transected at T(8-10) level, 2-3 weeks prior to performing an intravesical continuous infusion cystometrogram (CMG). Bladder volume threshold (VT) for inducing voiding and voiding efficiency (VE) were determined by measuring voided volumes and residual volumes (RV). After control CMGs were performed, cumulative intravenous doses of LY215490 (0.1, 1, and 10 mg/kg) or MK-801 (0.03, 0.3, and 3 mg/kg) were administered at 120-min intervals. Small doses of LY215490 (0.1 mg/kg) or MK-801 (0. 03 and 0.3 mg/kg) did not affect any parameters. A large dose (10 mg/kg) of LY215490 decreased maximal voiding pressure (MVP) by 27% and increased RV by 119% and VT by 58% but did not decrease VE. The highest cumulative dose (3 mg/kg) of MK-801 significantly increased RV by 134% and VT by 44% and markedly decreased VE by 60% and MVP by 18%. The effects of LY215490 to reduce MVP and increase VT without changing VE suggest that an AMPA receptor antagonist might be useful in treating detrusor-sphincter dyssynergia and bladder hypertrophy after SCI. The effect of MK-801 to markedly reduce VE indicates that NMDA receptor antagonists may exacerbate neurogenic bladder dysfunction in SCI patients.
Yoshiyama
M
M
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA.
Nezu
F M
FM
Yokoyama
O
O
Chancellor
M B
MB
de Groat
W C
WC
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D017470:Receptors, Glutamate / Q000502:physiology; D012018:Reflex / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D013777:Tetrazoles / Q000494:pharmacology*; D014521:Urethra / Q000294:innervation / Q000502:physiology; D001743:Urinary Bladder / Q000294:innervation; D014546:Urinary Catheterization; D014554:Urination / Q000187:drug effects*; D014563:Urodynamics
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D013777:Tetrazoles; D016291:Dizocilpine Maleate; C082309:tezampanel