Pharmacological Effect of TRK-380, a Novel Selective Human β3-Adrenoceptor Agonist, on Mammalian Detrusor Strips

Kanie, Sayoko; Otsuka, Atsushi; Morimoto, Takashi; Hareyama, Nana; Okazaki, Seiji; Kobayashi, Ryosuke; Hasebe, Ko; Nakao, Kaoru; Hayashi, Ryoji; Mochizuki, Hidenori; Matsumoto, Rikiya; Ozono, Seiichiro

doi:10.1016/j.urology.2011.08.080

Cited by 28 publications

(24 citation statements)

References 26 publications

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“…showed that procaterol, CL 316 243 and CGP‐12177A concentration‐dependently suppressed spontaneous or KCl‐induced contraction of the human ureter, and concluded that human ureteral relaxation was mainly mediated by β 2 ‐AR . More recently, however, CL 316 243 and CGP‐12177A have been reported to have a very low affinity for human β 3 ‐AR, and to have less potency than newly developed β 3 ‐AR agonists, such as mirabegron, AJ‐9677 and TRK‐380 . We are therefore unable to conclude that human ureteral relaxation is mainly mediated by β 2 ‐AR without confirming the relaxant effects of novel β 3 ‐AR agonists.…”

Section: Discussionmentioning

confidence: 82%

“…In their pharmacological studies, however, they applied CL 316 243 and CGP‐12177A as β 3 ‐AR agonists, which have both been recently reported to show a very low affinity to human β 3 ‐AR, and thus the question of whether human ureteral relaxation is mediated mainly by β 2 ‐AR remains unclear. More recently, novel selective β 3 ‐AR agonists, which have a high affinity for human β 3 ‐AR, such as mirabegron, AJ‐9677 and TRK‐380, have been synthesized, and are in clinical development for the treatment of overactive bladder . If these novel β 3 ‐AR agonists show sufficient potential to relax the human ureter, their use might become useful in the treatment of ureteral stones.…”

Section: Introductionmentioning

confidence: 99%

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Expression and functional role of β₃‐adrenoceptors in the human ureter

et al. 2013

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Abbreviations & AcronymsObjectives: To investigate the presence of b-adrenoceptor subtypes in the human ureter, and to examine whether b3-adrenoceptors modulate relaxation of the human ureter. Methods: Expression of messenger ribonucleic acid of b-adrenoceptors in the human ureter was determined by reverse transcription polymerase chain reaction, and distribution of b-adrenoceptors was examined by immunohistochemistry. In functional studies, the relaxant effects of isoproterenol, procaterol, TRK-380, salbutamol and BRL 37344 on KCl-induced contraction of the human ureter were evaluated, and the inhibitory effects of isoproterenol, procaterol and TRK-380 on electrical field stimulationinduced contractions were determined. Results: Expression of b1-, b2-and b3-adrenoceptor messenger ribonucleic acid in the human ureter was confirmed by reverse transcription polymerase chain reaction. Positive staining for b1-, b2-and b3-adrenoceptor was identified not only in smooth muscle, but also in the urothelium of the human ureter. All b-adrenoceptor agonists decreased the tone of KCl-induced contractions of the human ureter with a rank order of relaxant effects of isoproterenol > procaterol > TRK-380 > salbutamol > BRL 37344. Furthermore, isoproterenol, procaterol and TRK-380 significantly decreased the amplitude of electrical field stimulation-induced contractions with a rank order of inhibitory effects of isoproterenol > procaterol > TRK-380. Conclusions: Human ureteral relaxation is mediated by both b2-and b3-adrenoceptor stimulation. b3-Adrenoceptor agonists have the potential to relax the human ureter, and their clinical application in the treatment of ureteral stones is expected.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Expression and functional role of β₃‐adrenoceptors in the human ureter

et al. 2013

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“…It has been approved in Japan (Betanis ® , Astellas Pharma Inc, Tokyo, Japan) US (Myrbetriq ® , Astellas), and Europe (Betmiga ® , Astellas). However, several pharmaceutical companies are developing selective β 3 -adrenoceptor agonists for treatment of OAB 25,26. Except for the proof-of-concept studies of solabegron27 and ritobegron,25 clinical experiences with these agents are limited.…”

Section: Mirabegron: a β3-adrenoceptor Agonistmentioning

confidence: 99%

New developments in the management of overactive bladder: focus on mirabegron and onabotulinumtoxinA

Andersson¹

2013

TCRM

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In the last few years, much new information has been generated on the pathophysiology, possible therapeutic targets, and pharmacologic treatment of overactive bladder (OAB). Antimuscarinic drugs are still first-line pharmacologic treatment for OAB and often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, prompting a search for new therapeutic alternatives. Mirabegron and onabotulinumtoxinA, two drugs with different mechanisms of action, and with adverse effect profiles different from those of antimuscarinics, were recently approved for treatment of OAB. However, their place in the treatment of this disorder has not yet been established. In this short review, the mechanisms of action, clinical efficacy, and safety profiles of these drugs are discussed and compared with those of the current gold standard, antimuscarinic agents.

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“…The ability of β 3 -adrenoceptor agonists such as (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL37344), mirabegron (YM178), solabegron (GW427353), FK-175, TAK677, TRK-380, CL316243, and CGP12177A to inhibit detrusor smooth muscle (DSM) myogenic contractions has been well documented (Biers et al, 2006; Fujimura et al, 1999; Hicks et al, 2007; Hristov et al, 2008; Kanie et al, 2012; Kullmann et al, 2009; Leon et al, 2008; Sato et al, 2007; Takasu et al, 2007; Takeda et al, 1999; Tyagi et al, 2009). These β 3 -adrenoceptor agonists have been shown to increase the intracellular cAMP levels in native DSM tissues as well as in heterologously expressed systems (Fujimura et al, 1999; Hicks et al, 2007; Kanie et al, 2012; Kullmann et al, 2009; Sato et al, 2007; Takasu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…These β 3 -adrenoceptor agonists have been shown to increase the intracellular cAMP levels in native DSM tissues as well as in heterologously expressed systems (Fujimura et al, 1999; Hicks et al, 2007; Kanie et al, 2012; Kullmann et al, 2009; Sato et al, 2007; Takasu et al, 2007). Specifically, in rat DSM isolated strips, FK-175 has been shown to increase the intracellular cAMP level by ~30% (Fujimura et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Functional BK channels facilitate the β3-adrenoceptor agonist-mediated relaxation of nerve-evoked contractions in rat urinary bladder smooth muscle isolated strips

Afeli

Petkov

2013

European Journal of Pharmacology

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The large-conductance voltage- and Ca2+-activated K+ (BK) channel is a major regulator of detrusor smooth muscle (DSM) contractility thus facilitating urinary bladder function. Recent findings suggest that activation of β3-adrenoceptors causes DSM relaxation. However, it is unknown whether the β3-adrenoceptor-mediated DSM relaxation is BK channel-dependent during nerve-evoked contractions. To test this hypothesis, we induced nerve-evoked contractions in rat DSM isolated strips by using a tissue bath system equipped with platinum electrodes for electrical field stimulation (EFS). (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL37344), a β3-adrenoceptor agonist, significantly decreased the amplitude and muscle force of the 20 Hz EFS-induced DSM contractions in a concentration-dependent manner. The BRL37344 inhibitory effect was significantly antagonized by 1-(2-Ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1- naphthalenyl]amino]-(2S)-2-propanol hydrochloride (SR59230A), a β3-adrenoceptor antagonist. We further isolated the cholinergic from the purinergic component of the 0.5–50 Hz EFS-induced DSM contractions by using selective inhibitors, atropine as well as suramin and α,β- methylene-ATP, respectively. We found that BRL37344 inhibited both the purinergic and cholinergic components of the nerve-evoked contractions in rat DSM isolated strips. The pharmacological blockade of the BK channels with iberiotoxin, a selective BK channel inhibitor, increased the amplitude and muscle force of the 20 Hz EFS-induced contractions in rat DSM isolated strips. In the presence of iberiotoxin, there was a significant reduction in the BRL37344-induced inhibition of the 20 Hz EFS-induced contractions in rat DSM isolated strips. These latter findings suggest that BK channels play a critical role in the β3-adrenoceptor-mediated inhibition of rat DSM nerve-evoked contractions.

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Pharmacological Effect of TRK-380, a Novel Selective Human β3-Adrenoceptor Agonist, on Mammalian Detrusor Strips

Cited by 28 publications

References 26 publications

Expression and functional role of β₃‐adrenoceptors in the human ureter

Expression and functional role of β₃‐adrenoceptors in the human ureter

New developments in the management of overactive bladder: focus on mirabegron and onabotulinumtoxinA

Functional BK channels facilitate the β3-adrenoceptor agonist-mediated relaxation of nerve-evoked contractions in rat urinary bladder smooth muscle isolated strips

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Pharmacological Effect of TRK-380, a Novel Selective Human β3-Adrenoceptor Agonist, on Mammalian Detrusor Strips

Cited by 28 publications

References 26 publications

Expression and functional role of β3‐adrenoceptors in the human ureter

Expression and functional role of β3‐adrenoceptors in the human ureter

New developments in the management of overactive bladder: focus on mirabegron and onabotulinumtoxinA

Functional BK channels facilitate the β3-adrenoceptor agonist-mediated relaxation of nerve-evoked contractions in rat urinary bladder smooth muscle isolated strips

Contact Info

Product

Resources

About

Expression and functional role of β₃‐adrenoceptors in the human ureter

Expression and functional role of β₃‐adrenoceptors in the human ureter