Yuan C S, Foss J F, Moss J
Committee on Clinical Pharmacology, University of Chicago, IL 60637, USA.
Eur J Pharmacol. 1995 Mar 24;276(1-2):107-11. doi: 10.1016/0014-2999(95)00018-g.
We investigated the effects of methylnaltrexone on morphine-induced inhibition of smooth muscle-strip contraction in isolated guinea-pig ileum and human small intestine. The longitudinal muscle-strip was immersed in a temperature-controlled (37 degrees C) bath containing a physiological solution of 95% O2 and 5% CO2 with pH 7.4. Muscle contraction was elicited by transmural electrical stimulation with a pulse duration of 0.5 ms at frequencies of 1-50 Hz for 5-10 s at 1-3-min intervals. Muscle contraction was blocked by tetrodotoxin or atropine in both preparations. When methylnaltrexone was applied to the bath, the force produced by muscle contraction was enhanced up to approximately 30%. Stimulation-elicited muscle contraction was inhibited by morphine, which decreased the force of contraction 42 +/- 9.5% (S.D.) in the human intestine preparation and 35 +/- 8.6% in guinea-pig ileum at the inhibitory concentration 70% (IC70). Methylnaltrexone effectively antagonized the effects of morphine-induced inhibition of muscle-strip contraction. In the guinea-pig ileum preparation, methylnaltrexone at 30, 100 and 300 nM blocked 25 +/- 10.5%, 74 +/- 7.2% and 89 +/- 9.9% of morphine-induced (300 nM) inhibition, respectively. In the human intestine preparation, methylnaltrexone at the same concentrations blocked 57 +/- 10.9%, 74 +/- 12.9% and 92 +/- 7.2% of morphine-induced (100 nM) inhibition, respectively. The relative ratio of methylnaltrexone to morphine was higher in human intestine (1:1) than in the guinea-pig ileum preparation (1:3). These data provide preliminary information for clinical studies to evaluate the efficacy of methylnaltrexone in preventing or reducing morphine-induced antimotility and antitransit actions.
我们研究了甲基纳曲酮对吗啡诱导的豚鼠离体回肠和人小肠平滑肌条收缩抑制作用的影响。纵行肌条浸于温度控制在37℃的浴槽中，浴槽内含有95% O₂和5% CO₂、pH 7.4的生理溶液。通过跨壁电刺激引发肌肉收缩，脉冲持续时间为0.5毫秒，频率为1 - 50赫兹，每次刺激5 - 10秒，间隔1 - 3分钟。两种标本中的肌肉收缩均被河豚毒素或阿托品阻断。当将甲基纳曲酮加入浴槽时，肌肉收缩产生的力量增强了约30%。刺激引发的肌肉收缩被吗啡抑制，在抑制浓度70%（IC70）时，吗啡使人体肠道标本中的收缩力降低了42±9.5%（标准差），使豚鼠回肠中的收缩力降低了35±8.6%。甲基纳曲酮有效地拮抗了吗啡诱导的肌肉条收缩抑制作用。在豚鼠回肠标本中，30、100和300 nM的甲基纳曲酮分别阻断了吗啡诱导的（300 nM）抑制作用的25±10.5%、74±7.2%和89±9.9%。在人体肠道标本中，相同浓度的甲基纳曲酮分别阻断了吗啡诱导的（100 nM）抑制作用的57±10.9%、74±12.9%和92±7.2%。甲基纳曲酮与吗啡的相对比例在人体肠道中（1:1）高于豚鼠回肠标本中（1:3）。这些数据为临床研究提供了初步信息，以评估甲基纳曲酮在预防或减轻吗啡诱导的抗蠕动和抗转运作用方面的疗效。
