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  • TRK-380, a novel selective human β3-adrenoceptor agonist, ameliorates formalin-induced pollakiuria in rats and carbachol-induced bladder contraction in dogs.

TRK-380, a novel selective human β3-adrenoceptor agonist, ameliorates formalin-induced pollakiuria in rats and carbachol-induced bladder contraction in dogs.

Urology (2013-10-01)
Sayoko Kanie, Atsushi Otsuka, Satoru Yoshikawa, Ryosuke Kobayashi, Shoichi Itaba, Hiroshi Yokokawa, Yoriko Tajima, Seiichiro Ozono, Ryoji Hayashi, Hidenori Mochizuki
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Carbamoylcholine chloride, ≥98% (titration), crystalline
Supelco
Formaldehyde solution, stabilized with methanol, ~37 wt. % in H2O, certified reference material
Sigma-Aldrich
Formaldehyde solution, ACS reagent, 37 wt. % in H2O, contains 10-15% Methanol as stabilizer (to prevent polymerization)
Sigma-Aldrich
Formaldehyde solution, tested according to Ph. Eur.
Sigma-Aldrich
Formaldehyde solution, meets analytical specification of USP, ≥34.5 wt. %
Sigma-Aldrich
Formaldehyde solution, for molecular biology, BioReagent, ≥36.0% in H2O (T)
Sigma-Aldrich
Formaldehyde solution, for molecular biology, 36.5-38% in H2O
Sigma-Aldrich
Formaldehyde solution, meets analytical specification of Ph. Eur., BP, 35 wt. %, contains 10% methanol as stabilizer
SAFC
Formaldehyde solution, contains 10-15% methanol as stabilizer, 37 wt. % in H2O
Carbachol, European Pharmacopoeia (EP) Reference Standard