Yoshiyama M, Nezu F M, Yokoyama O, Chancellor M B, de Groat W C
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA.
Exp Neurol. 1999 Sep;159(1):250-7. doi: 10.1006/exnr.1999.7124.
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.
本研究旨在确定α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（LY215490）或N-甲基-D-天冬氨酸（MK-801）谷氨酸能受体拮抗剂是否能减轻与逼尿肌反射亢进和逼尿肌-括约肌协同失调相关的尿路功能障碍，实验对象为清醒的脊髓损伤（SCI）大鼠。实验选用雌性Sprague-Dawley大鼠，在进行膀胱内连续灌注膀胱测压（CMG）前2至3周，将其脊髓在T(8 - 10)水平完全横断。通过测量排尿量和残余尿量（RV）来确定诱发排尿的膀胱容量阈值（VT）和排尿效率（VE）。在进行对照CMG后，以120分钟的间隔静脉注射累积剂量的LY215490（0.1、1和10毫克/千克）或MK-801（0.03、0.3和3毫克/千克）。小剂量的LY215490（0.1毫克/千克）或MK-801（0.03和0.3毫克/千克）对任何参数均无影响。大剂量（10毫克/千克）的LY215490使最大排尿压力（MVP）降低27%，RV增加119%，VT增加58%，但未降低VE。MK-801的最高累积剂量（3毫克/千克）使RV显著增加134%，VT增加44%，VE显著降低60%，MVP降低18%。LY215490降低MVP并增加VT而不改变VE的作用表明，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂可能有助于治疗脊髓损伤后的逼尿肌-括约肌协同失调和膀胱肥大。MK-801显著降低VE的作用表明，N-甲基-D-天冬氨酸受体拮抗剂可能会加重脊髓损伤患者的神经源性膀胱功能障碍。
