Biol. Pharm. Bull. 42(7): 1064-1068 (2019)

1064 Biol. Pharm. Bull. 42, 1064–1068 (2019) Vol. 42, No. 7 Review Effects of Distigmine on the Mechanical Activity of Urinary Bladder Smooth Muscle Keisuke Obara* and Yoshio Tanaka Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan. Received February 28, 2019; accepted April 24, 2019 Distigmine bromide (distigmine) is a reversible carbamate cholinesterase (ChE) inhibitor. Its principle clinical application is in the treatment of myasthenia gravis. Distigmine is also used as a remedy for dysuria and glaucoma. Its effectiveness in the management of dysuria has been demonstrated in several clinical re- ports. Distigmine may improve (enhance) urinary bladder smooth muscle (UBSM) contraction during mic- turition by inhibiting acetylcholine (ACh) decomposition. However, the pharmacological effects of distigmine on UBSM have not been adequately studied so far. In this review article, we summarize the reported effects of distigmine on the contractile responses elicited by exogenous and endogenous ACh in isolated UBSM preparations. We also discuss the effects of distigmine on the UBSM basal tone and the contractile response of UBSM to ATP, which is co-released with ACh from parasympathetic nerve terminals. Key words distigmine bromide; urinary bladder smooth muscle; cholinesterase inhibitor; acetylcholine; adenosine triphosphate 1. INTRODUCTION 2. EFFECTS OF DISTIGMINE ON UBSM CONTRAC- TILE RESPONSES ELICITED BY EXOGENOUS CON- Distigmine bromide (distigmine) is a carbamate cholinester- STRICTORS ase(ChE)inhibitorfirstsynthesizedbySchmidinthe1950s1) (Fig. 1). It and other carbamate ChE inhibitors have been used During urination, ACh and ATP are released from the to treat myasthenia gravis in Asia, the Middle East, and Eu- parasympathetic nerve ending in the UB in response to rope.2–5) Distigmine has also been used to treat glaucoma in nerve excitation.30–36) Distigmine inhibits acetylcholinesterase Japan.6–8) Distigmine has also been applied as a remedy for (AChE) activity in the UB.37,38) Therefore, it is presumed that dysuria in Japan since its release there in 1968. It was report- distigmine enhances the contractile force of the UBSM by ed that distigmine has a therapeutic effect on neurogenically increasing ACh concentration in the synaptic cleft between underactive bladder caused by surgery, spinal cord injury, the parasympathetic nerve ending and the UBSM. To test and chronic diseases such as diabetes.9–21) It is also effective this assumption, we investigated the effects of distigmine on against drug-induced dysuria22,23) and benign prostatic hyper- ACh-induced contractions in guinea pig UBSM. As shown in plasia (BPH)-induced dysuria.24–26) Distigmine was reported Fig. 2A, distigmine (3 × 10−8−3 × 10−6 M) enhanced the ACh- to be clinically effective against both underactive bladder and induced contractile response in the UBSM in a concentration- dysuria. In recent years, distigmine efficacy was validated dependent manner.39–41) with various animal disease models.27–29) A study using the balloon method reported that distigmine The therapeutic effect of distigmine in the management potentiated the increase in guinea pig intravesical pressure of urinary disorders is explained by its ChE inhibition. This induced by intravenous ACh administration.39) The duration of mechanism enhances the contractile force of the urinary the enhancement of ACh-induced guinea pig UB contraction bladder smooth muscle (UBSM) by increasing the concentra- by distigmine was commensurate with its inhibitory effect on tion of acetylcholine (ACh) in the synaptic cleft between the ChE in the UB.42) These results, then, support the presumption parasympathetic nerve terminal and the UBSM. However, the that distigmine enhances the contractile force of UBSM by pharmacological effects of distigmine on the UBSM have sel- increasing ACh. dom been investigated despite the fact that numerous clinical ATP is also a parasympathetic UBSM constrictor. Thus, we reportshavedemonstrateditsefficacyindysuriatreatment.In also examined the effect of distigmine on ATP-induced guinea this review article, we present a synopsis of studies in which the effects of distigmine on the contractile responses elicited by exogenous and endogenous ACh were examined in isolated UBSM preparations. We also discuss the effects of distigmine on the UBSM basal tone and the contractile response of UBSM to the neurotransmitter ATP, which is co-released with ACh from the parasympathetic nerve terminals. Fig. 1. Structure of Distigmine Bromide (Distigmine) * To whom correspondence should be addressed. e-mail: [email protected] © 2019 The Pharmaceutical Society of Japan Vol. 42, No. 7 (2019) Biol. Pharm. Bull. 1065 Fig. 2. Effects of Distigmine on Concentration-Response Curves for Acetylcholine (ACh) (A) and ATP (B)-Induced Contraction of Guinea Pig Uri- nary Bladder Smooth Muscle ACh and ATP were cumulatively added to the bath solution either in the absence or presence of distigmine. Ordinate: % contraction induced by 3 × 10−4 M acetylcholine in the absence of drugs (A) or by a single administration of 10−4 M ATP before the experiment (B). Abscissa: negative logarithms of acetylcholine (A) or ATP (B) concentrations (M). Data are means ± S.E.M. for n = 4–24 experiments. ** p < 0.01 vs. control. Data were reproduced with permission of the authors of Ōyō Yakuri/Pharmacomet- rics, 85, 101–114 (2013)41) (Fig. 2A) and Biol. Pharm. Bull., 40, 1092–1100 (2017)42) (Fig. 2B). pig UBSM contractile response. However, distigmine (10−6 M) mediated by the release of endogenous ACh from the para- had no effect on the ATP concentration-response curves in sympathetic nerve terminals without affecting ATP-mediated guinea pig UBSM42) (Fig. 2B). contraction. Similar results were obtained for mouse bladder.45) 3. EFFECTS OF DISTIGMINE ON UBSM CONTRAC- 4. EFFECTS OF DISTIGMINE ON THE BASAL TONE TILE RESPONSES ELICITED BY ENDOGENOUS OF UBSM PARASYMPATHETIC NEUROTRANSMITTERS Very close observation disclosed that distigmine marginally In human UBSM, distigmine may enhance contractile increased the basal tone of guinea pig UBSM39–41,46) (Fig. 4). responses to parasympathetic nerve excitement induced by Distigmine also very slightly increased basal tone in human electrical field stimulation (EFS).43) However, it is unknown UBSM.4) In contrast, the carbamate ChE inhibitors neostig- which endogenous parasympathetic neurotransmitters cause mine and pyridostigmine strongly enhanced the basal tone this potentiation. Guinea pig UBSM contractile responses to of guinea pig UBSM39,40,46) (Fig. 4). This discrepancy may be EFS consisted of a contractile component sensitive to the mus- resolved by the fact that whereas neostigmine and pyridostig- carinic receptor antagonist atropine and another affected by mine are exclusively cholinergic, distigmine may also have a the purinergic receptor-desensitizing agent α,β-methylene ATP paradoxical anticholinergic effect. In rat bladder, distigmine (α,β-mATP). The application concentrations of these agents inhibited the binding of [3H] N-methyl scopolamine to the −6 −4 were 10 and 10 M, respectively (Fig. 3A). Therefore, these muscarinic receptors. Its Ki value was 1.33 ± 0.11 µM whereas contractions were caused by both ACh (the atropine-sensitive that for neostigmine was >50µM. Therefore, the latter should component) and ATP (the α,β-mATP-sensitive component).44) have no effect on the muscarinic receptors.47) Our mechanistic To confirm that distigmine augments the ACh-induced study demonstrated that distigmine (3 × 10−5 M) suppressed contractile component, we examined its effects on contraction bethanechol-induced contractile responses in guinea pig generated in the presence of α,β-mATP (10−4 M). Distigmine UBSM and urethral smooth muscle.39) Bethanechol is a syn- (10−6 M) substantially enhanced the contractile component thetic choline ester which is not decomposed by ChE. and subsequent atropine (10−6 M) administration almost com- ChE inhibitors may increase UBSM basal tone by stimulat- pletely suppressed it (Fig. 3B). Therefore, distigmine clearly ing the release of ACh from parasympathetic nerve endings. augmented the ACh-mediated contractile component.44) This mechanism was inferred from the effects of ChE inhibi- We also examined the effects of distigmine on the EFS- tors on nicotine receptors. Distigmine and neostigmine inhibit induced contractile component generated in the presence of the binding of [3H] epibatidine to nicotine receptors in rat ce- atropine to verify that distigmine does not influence ATP- rebral cortex. The Ki values were 22.9 ± 3.3 µM for distigmine induced contraction. Distigmine (10−6M) did not significantly and 18.8 ± 3.3 µM for neostigmine.47) We investigated whether affect the contractile component generated in the presence neostigmine mediated the increase in UBSM basal tone via of atropine (10−6 M) (p >0.05 for atropine (10−6 M) vs. atro- ACh derived from parasympathetic nerves. This effect was pine (10−6 M) + distigmine (10−6 M)). In fact, the contractile not significantly affected by tetrodotoxin (TTX; 10−6 M) component generated in the presence of atropine was me- (p >0.05 for neostigmine (3× 10−5 M) vs. neostigmine diated by ATP because it was significantly suppressed by (3 × 10−5 M) + TTX (10−6 M)) (our unpublished observation). α,β-mATP (10−4 M) (p <0.05foratropine(10−6 M) vs. atropine Therefore, ACh derived from the parasympathetic nerves (10−6 M) + distigmine

Load more