Nagabukuro Hiroshi, Doi Takayuki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-17-85, Jusohonmachi, Osaka, 532-8686, Japan.
Life Sci. 2005 Nov 12;77(26):3276-86. doi: 10.1016/j.lfs.2005.04.028. Epub 2005 Jun 22.
The aim of this study was to compare the effects of TAK-802, a novel acetylcholinesterase (AChE) inhibitor, and carbamate AChE inhibitors on the detrusor smooth muscle contractility in vitro using isometric tension measurements. The effects of drugs on the nicotine-induced contractions and basal tone of the isolated detrusor muscle of the guinea pig were examined. All of the drugs, namely, TAK-802, distigmine, neostigmine and pyridostigmine, enhanced the nicotine-induced contractions of the muscle strips in a concentration-dependent manner. On the other hand, while neostigmine and pyridostigmine markedly increased the basal tone, and distigmine slightly but significantly increased the basal tone, TAK-802 had no influence on the basal tone of the muscle strips at all. However, following co-treatment with tetraisopropyl pyrophosphoramide, a selective butyrylcholinesterase (BuChE) inhibitor, TAK-802 also did increase the basal tone. The increase of the basal tone by all of the above treatments was completely abolished by atropine. These results reveal that while all the four AChE inhibitors enhanced endogenous acetylcholine-induced contractions, their effects on the basal tone were clearly different. The effect of carbamate AChE inhibitors of increasing the basal tone could be partly attributed to their dual inhibition of both AChE and BuChE, because both cholinesterases may play a critical role in maintaining the resting tension of the urinary bladder. TAK-802, however, did not increase the basal tone of the detrusor muscle strips, probably because of its selective inhibitory effect against AChE. The effect of carbamate AChE inhibitors on the basal tone of the detrusor muscle may explain the decrease of bladder compliance observed in our previous study on guinea pigs as well as the deterioration of the bladder-storage function reported with their clinical use.
本研究旨在通过等长张力测量，比较新型乙酰胆碱酯酶（AChE）抑制剂TAK - 802与氨基甲酸酯类AChE抑制剂对体外逼尿肌平滑肌收缩力的影响。检测了药物对豚鼠离体逼尿肌尼古丁诱导的收缩和基础张力的影响。所有药物，即TAK - 802、地斯的明、新斯的明和吡啶斯的明，均以浓度依赖性方式增强了肌肉条带尼古丁诱导的收缩。另一方面，新斯的明和吡啶斯的明显著增加基础张力，地斯的明轻微但显著增加基础张力，而TAK - 802对肌肉条带的基础张力完全没有影响。然而，在与选择性丁酰胆碱酯酶（BuChE）抑制剂四异丙基焦磷酰胺联合处理后，TAK - 802也确实增加了基础张力。上述所有处理引起的基础张力增加均被阿托品完全消除。这些结果表明，虽然所有四种AChE抑制剂均增强了内源性乙酰胆碱诱导的收缩，但其对基础张力的影响明显不同。氨基甲酸酯类AChE抑制剂增加基础张力的作用可能部分归因于它们对AChE和BuChE的双重抑制，因为两种胆碱酯酶可能在维持膀胱静息张力中起关键作用。然而，TAK - 802并未增加逼尿肌条带的基础张力，可能是由于其对AChE的选择性抑制作用。氨基甲酸酯类AChE抑制剂对逼尿肌基础张力的影响可能解释了我们先前在豚鼠研究中观察到的膀胱顺应性降低以及其临床使用中报道的膀胱储存功能恶化。
