Effect of distigmine on the contractile response of guinea pig urinary bladder to electrical field stimulation

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 (10^-6M), and the remaining contractile components in the presence of atropine were virtually abolished by α,β-methylene adenosine triphosphate (α,β-mATP) (10^-4M). Distigmine (10^-6M) significantly potentiated EFS-induced contractile components generated in the presence of α,β-mATP (10^-4M), but did not potentiate EFS-induced contractile components generated in the presence of atropine (10^-6M). 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.