Obara Keisuke, Kobayashi Yurina, Chino Daisuke, Tanaka Yoshio
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi-City, Chiba 274-8510, Japan.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi-City, Chiba 274-8510, Japan.
Eur J Pharmacol. 2017 Aug 15;809:209-214. doi: 10.1016/j.ejphar.2017.05.031. Epub 2017 May 13.
Distigmine bromide (distigmine) is a reversible carbamate group cholinesterase (ChE) inhibitor. Although mainly used clinically for the treatment of myasthenia gravis, distigmine is also indicated for detrusor underactivity in Japan. According to the pharmacological classification of distigmine, its therapeutic effect against detrusor underactivity appears to be produced by enhanced urinary bladder smooth muscle (UBSM) contractility due to an increased concentration of acetylcholine between parasympathetic nerve endings and UBSM cells. However, ATP as well as acetylcholine is also released from parasympathetic nerve endings that dominate UBSM. The present study was thus carried out to investigate the potentiating effects of distigmine on the two UBSM contractile components in response to parasympathetic nerve stimulation induced by electrical field stimulation (EFS). In isolated guinea pig UBSM tissues, EFS (1-16Hz) produced tetrodotoxin-sensitive, frequency-dependent contractions. The contractile responses to EFS were largely diminished by atropine (10M), and the remaining contractile components in the presence of atropine were virtually abolished by α,β-methylene adenosine triphosphate (α,β-mATP) (10M). Distigmine (10M) significantly potentiated EFS-induced contractile components generated in the presence of α,β-mATP (10M), but did not potentiate EFS-induced contractile components generated in the presence of atropine (10M). These findings clearly indicate that distigmine strongly potentiates UBSM contraction selectively induced by parasympathetic nerve-derived acetylcholine, suggesting a potential mechanism by which distigmine restores detrusor underactivity.
溴化双斯的明是一种可逆性氨基甲酸酯类胆碱酯酶（ChE）抑制剂。虽然溴化双斯的明主要在临床上用于治疗重症肌无力，但在日本也被用于治疗逼尿肌活动不足。根据溴化双斯的明的药理分类，其对逼尿肌活动不足的治疗作用似乎是由于副交感神经末梢与膀胱平滑肌（UBSM）细胞之间乙酰胆碱浓度增加，从而增强了膀胱平滑肌收缩力。然而，三磷酸腺苷（ATP）以及乙酰胆碱也从支配UBSM的副交感神经末梢释放。因此，本研究旨在探讨溴化双斯的明对电场刺激（EFS）诱导的副交感神经刺激所引起的两种UBSM收缩成分的增强作用。在分离的豚鼠UBSM组织中，EFS（1-16Hz）可产生对河豚毒素敏感的频率依赖性收缩。阿托品（10μM）可使对EFS的收缩反应大幅减弱，在阿托品存在的情况下，剩余的收缩成分几乎可被α,β-亚甲基三磷酸腺苷（α,β-mATP）（10μM）消除。溴化双斯的明（10μM）可显著增强在α,β-mATP（10μM）存在时EFS诱导的收缩成分，但不能增强在阿托品（10μM）存在时EFS诱导的收缩成分。这些发现清楚地表明，溴化双斯的明强烈增强由副交感神经源性乙酰胆碱选择性诱导的UBSM收缩，提示了溴化双斯的明恢复逼尿肌活动不足的潜在机制。
