Differential effects of TAK-802, a selective acetylcholinesterase inhibitor, and carbamate acetylcholinesterase inhibitors on contraction of the detrusor smooth muscle of the guinea pig.
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.
Nagabukuro
Hiroshi
H
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-17-85, Jusohonmachi, Osaka, 532-8686, Japan. nagabukuro_hiroshi@takeda.co.jp
Doi
Takayuki
T
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D007537:Isometric Contraction / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009130:Muscle, Smooth / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D001743:Urinary Bladder / Q000502:physiology
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D011758:Pyrroles; D015363:Quinolones; D009538:Nicotine; C496138:8-(3-(1-((3-fluorophenyl)methyl)-4-piperidinyl)-1-oxopropyl)-1,2,5,6-tetrahydro-4H-pyrrolo(3,2,1-ij)quinolin-4-one; D000110:Acetylcholinesterase