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

Abstract

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.

Conclusion: 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.