Nagabukuro Hiroshi, Okanishi Satoshi, Doi Takayuki
Pharmaceutical Research Division, Takeda Chemical Industries, 2-17-85, Jusohonmachi, Yodogawa, Osaka 532-8686, Japan.
Eur J Pharmacol. 2004 Jun 28;494(2-3):225-32. doi: 10.1016/j.ejphar.2004.05.007.
In the present study, we investigated the effects of cholinomimetic drugs on the urodynamic characteristics in anesthetized guinea pigs. 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (TAK-802), a novel acetylcholinesterase inhibitor, (0.003-0.03 mg/kg, i.v.) increased the voided volume and the maximum flow rate without affecting either the intravesical pressure or the bladder compliance. Distigmine (0.03-0.3 mg/kg, i.v.) and neostigmine (0.01-0.1 mg/kg, i.v.), both carbamate acetylcholinesterase inhibitors, while not increasing the maximum flow rate, increased the intravesical pressure at the maximum flow rate. They also decreased the bladder compliance. Bethanechol (0.1-1 mg/kg, i.v.), a muscarinic receptor agonist, decreased the voided volume and the bladder compliance but did not affect the maximum flow rate. TAK-802 did not affect the intraurethral pressure at doses of up to 0.03 mg/kg in anesthetized guinea pigs. Distigmine increased the intraurethral pressure when administered at the dose of 0.3 mg/kg, and the effect was completely abolished by pretreatment with d-tubocurarine. These results suggest that TAK-802 reinforces the bladder-voiding functions by increasing the bladder contractility without decreasing the storage function. On the other hand, carbamate acetylcholinesterase inhibitors not only deteriorate the voiding function by inducing contraction of the external urethral sphincter muscle, resulting in increasing the urethral resistance, but also cause deterioration of the storage function. Bethanechol obviously decreased the bladder capacity, possibly due to a direct contractile effect on the detrusor smooth muscle. TAK-802 may therefore be a more useful drug than either carbamate acetylcholinesterase inhibitors or muscarinic receptor agonists in the treatment of voiding dysfunction associated with impaired detrusor contractility.
在本研究中，我们研究了拟胆碱药物对麻醉豚鼠尿动力学特征的影响。新型乙酰胆碱酯酶抑制剂8-[3-[1-[(3-氟苯基)甲基]-4-哌啶基]-1-氧代丙基]-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-4-酮（TAK-802）（0.003 - 0.03 mg/kg，静脉注射）增加了排尿量和最大尿流率，而不影响膀胱内压或膀胱顺应性。氨基甲酸酯类乙酰胆碱酯酶抑制剂地斯的明（0.03 - 0.3 mg/kg，静脉注射）和新斯的明（0.01 - 0.1 mg/kg，静脉注射）虽然没有增加最大尿流率，但在最大尿流率时增加了膀胱内压。它们还降低了膀胱顺应性。毒蕈碱受体激动剂氨甲酰甲胆碱（0.1 - 1 mg/kg，静脉注射）减少了排尿量和膀胱顺应性，但不影响最大尿流率。在麻醉豚鼠中，剂量高达0.03 mg/kg时，TAK-802不影响尿道内压。地斯的明以0.3 mg/kg剂量给药时会增加尿道内压，且该作用可被筒箭毒碱预处理完全消除。这些结果表明，TAK-802通过增加膀胱收缩力而不降低储存功能来增强膀胱排尿功能。另一方面，氨基甲酸酯类乙酰胆碱酯酶抑制剂不仅通过诱导尿道外括约肌收缩导致尿道阻力增加而使排尿功能恶化，还会导致储存功能恶化。氨甲酰甲胆碱明显降低了膀胱容量，这可能是由于其对逼尿肌平滑肌的直接收缩作用。因此，在治疗与逼尿肌收缩力受损相关的排尿功能障碍方面，TAK-802可能比氨基甲酸酯类乙酰胆碱酯酶抑制剂或毒蕈碱受体激动剂更有用。
