title: Effects of TAK-802, a novel acetylcholinesterase inhibitor, and various cholinomimetics on the urodynamic characteristics in anesthetized guinea pigs.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, 2-17-85, Jusohonmachi, Yodogawa, Osaka 532-8686, Japan. nagabukuro_hiroshi@takeda.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okanishi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
mesh_terms: D000758:Anesthesia; D018686:Anesthetics, Intravenous; D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D011312:Pressure; D011758:Pyrroles / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D014520:Urethane; D014521:Urethra / Q000187:drug effects / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects*
chemical_list: D018686:Anesthetics, Intravenous; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D011758:Pyrroles; D015363:Quinolones; D014520:Urethane; 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