TRK-380, a novel selective human β3-adrenoceptor agonist, ameliorates formalin-induced pollakiuria in rats and carbachol-induced bladder contraction in dogs.
OBJECTIVE
To investigate the effects of TRK-380, a selective β3-adrenoceptor (β3-AR) agonist, on voiding behavior in rats with pollakiuria and on carbachol (CCh)-induced bladder contraction in dogs.


METHODS
The voiding behavior of female Sprague Dawley rats was recorded continuously with a balance. Rats were intravesically pretreated with 2.5% formalin under isoflurane anesthesia. The next day, the effect of TRK-380 (7.5-30 mg/kg, orally) or tolterodine, an antimuscarinic drug (3.75-15 mg/kg, orally), on the voiding frequency was evaluated. In another experiment, male beagle dogs were anesthetized with pentobarbital, CCh (3 μg/kg, intravenously) was administered to them, and the effect of TRK-380 (0.1 or 0.3 μg/kg/minute, intravenously infusion) on CCh-induced bladder contraction was evaluated.


RESULTS
Rats treated with formalin showed a significant increase in the voiding frequency compared with the sham group, and the increase in it was significantly and dose-dependently suppressed by TRK-380 at doses of ≥15 mg/kg. In contrast, tolterodine did not lead to a significant change in the voiding frequency even at the highest dose. In dogs, CCh-induced bladder contraction was dose-dependently suppressed by TRK-380; the plasma concentration required for 30% suppression of the CCh-induced bladder contraction (30% relaxation) was 4.90 ng/mL.


CONCLUSIONS
This study indicated that TRK-380 ameliorated pollakiuria, which was resistant to an antimuscarinic drug, and that it also suppressed the bladder contraction induced by cholinergic stimulation in dogs, whose bladder relaxation is known to be predominantly mediated by β3-ARs, as in humans. These data strengthen the therapeutic potential of β3-AR for the treatment of overactive bladder.
Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Japan. Electronic address: Sayoko_Kanie@nts.toray.co.jp.
Sayoko
S
Kanie
Atsushi
A
Otsuka
Satoru
S
Yoshikawa
Ryosuke
R
Kobayashi
Shoichi
S
Itaba
Hiroshi
H
Yokokawa
Yoriko
Y
Tajima
Seiichiro
S
Ozono
Ryoji
R
Hayashi
Hidenori
H
Mochizuki
D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000008:administration & dosage; D018679:Cholinergic Agonists / Q000008:administration & dosage; D004285:Dogs; D005260:Female; D005557:Formaldehyde / Q000008:administration & dosage; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology*; D014554:Urination / Q000187:drug effects*; D014555:Urination Disorders / Q000139:chemically induced / Q000188:drug therapy*
D058667:Adrenergic beta-3 Receptor Agonists; D018679:Cholinergic Agonists; D005557:Formaldehyde; D002217:Carbachol