Effects of the selective acetylcholinesterase inhibitor TAK-802 on the voiding behavior and bladder mass increase in rats with partial bladder outlet obstruction.
OBJECTIVE
We examined the effects of the selective acetylcholinesterase (AChE) inhibitor TAK-802 on voiding behavior and residual urine volume in rats with partial bladder outlet obstruction (BOO) vs rats treated with the nonselective AChE inhibitor distigmine and the muscarinic agonist bethanechol. In addition, the effect of repeat doses of TAK-802 on the bladder mass increase associated with BOO was also examined.


METHODS
Male rats with BOO were used. Six to 8 days after obstruction voiding behavior was observed in a metabolic cage. The animals were then treated orally with 1 drug, and voiding frequency and urine volume at each void were measured for 3 hours. Subsequently the volume of urine retained in the bladder (residual urine) was measured. In another experiment bladder weight in rats with BOO was measured after early repeat doses of TAK-802.


RESULTS
BOO increased voiding frequency and decreased average voided volume. TAK-802 and distigmine increased average voided volume, while not causing any change in voiding frequency. On the other hand, bethanechol increased voiding frequency without affecting average voided volume. While all 3 drugs significantly decreased residual urine volume, TAK-802 was most efficacious. In addition, bladder weight in the control BOO group was greater (approximately 2.2-fold) than that in the sham operated group and early repeat administration of TAK-802 prevented the bladder mass increase.


CONCLUSIONS
AChE inhibitors decreased residual urine volume by restoring voiding function in rats with BOO, although only the effect of TAK-802 was dose dependent. Bethanechol also decreased residual urine volume in a dose dependent manner but by increasing voiding frequency. The prevention of a bladder mass increase by TAK-802 treatment may be attributable to its effect on restoring voiding.
Hashimoto
Tadatoshi
T
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Nagabukuro
Hiroshi
H
Doi
Takayuki
T
D000284:Administration, Oral; D000818:Animals; D018723:Bethanechol / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011726:Pyridinium Compounds / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*; D014554:Urination / Q000187:drug effects / Q000528:radiation effects; D014563:Urodynamics / Q000187:drug effects* / Q000502:physiology
D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D011726:Pyridinium Compounds; D011758:Pyrroles; D015363:Quinolones; D018723:Bethanechol; 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; C084645:distigmine