Effects of a novel β₃‐adrenoceptor agonist, AJ‐9677, on relaxation of the detrusor muscle: An in vitro study

Abstract

Objectives:To examine the relaxant effects of AJ-9677, a novel b3-adrenoceptor agonist, on the isolated rat, monkey and human detrusor muscle. Methods: The isolated detrusor strips of rats, monkeys and humans were mounted in organ baths containing Krebs solution. By the cumulative addition of b-adrenoceptor agonists (isoproterenol, AJ-9677, CL 316,243 and salbutamol in rats; isoproterenol, AJ-9677 and CL 316,243 in monkeys and humans), concentration-relaxation curves were obtained. The maximal relaxation responses and pEC50 values were calculated. In rats, concentration-relaxation curves to isoproterenol and AJ-9677 were obtained in the presence and absence of propranolol or SR 59230A. Results: Isoproterenol, AJ-9677, CL 316,243 and salbutamol induced concentration-dependent relaxation in rats. The rank order of their relaxing potency in the rat detrusor muscle was AJ-9677 > isoproterenol > CL 316,243 > salbutamol. Isoproterenol and AJ-9677 also produced a concentration-dependent relaxation with high potency in monkeys and humans, whilst CL 316,243 had low relaxing potency. According to the antagonist studies in rats, propranolol and SR 59230A caused a rightward shift of the concentration-relaxation curves to isoproterenol or AJ-9677, respectively. Conclusions: AJ-9677 has a high relaxant potency on the rat, monkey and human detrusor smooth muscle, and it may have the potential to treat overactive bladder.

Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322

“…Thus, isoproterenol responses were inhibited by SR58894 but only poorly by CGP 20712A or ICI 118551 (Igawa et al 1999) or inhibited by SR59230A but only poorly by atenolol or butoxamine . Antagonism of isoproterenol responses by SR59230A has also been reported by others in isolated human bladder strips (Otsuka et al 2008a;Frazier et al 2011) and was reproduced in our present study. On the other hand, SR59230A yielded only limited inhibition of the human detrusor relaxation response to solabegron (Biers et al 2006) or nebivolol (Frazier et al 2011).…”

“…Based on the potency and efficacy of the reference agonists isoproterenol, noradrenaline, and adrenaline; the β1-agonist dobutamine; the β2-agonists clenbuterol, procaterol, salbutamol, and terbutaline; and the β3-agonists 138- 17, 4.79±0.38, and 5.59±0.72, respectively 355, AJ-9677, BRL 37344, CL-316243, GS 332, L 755,507, mirabegron, solabegron, and ZD 7114, it has generally been claimed that human detrusor smooth muscle relaxation is a β3-AR-mediated response (Badawi et al 2005(Badawi et al , 2007Biers et al 2006;Igawa et al 1998Igawa et al , 1999Igawa et al , 2001Li et al 2003;Morita et al 2000;Nomiya and Yamaguchi 2003;Otsuka et al 2008a;Takasu et al 2007;Takeda et al 1999;Yamanishi et al 2006). The potency and efficacy of isoproterenol, clenbuterol, and BRL 37344 in the present study is in line with those previous reports and validates our preparation.…”

“…Accordingly, several studies based on the potency and efficacy of several subtype-selective agonists have indicated that relaxation of human detrusor smooth muscle occurs primarily via β3-AR (Badawi et al 2005(Badawi et al , 2007Biers et al 2006;Igawa et al 1998Igawa et al , 1999Igawa et al , 2001Li et al 2003; Morita et al 2000;Nomiya and Yamaguchi 2003;Otsuka et al 2008a;Takasu et al 2007;Takeda et al 1999;Yamanishi et al 2006). Confirmation of these findings by subtype-selective antagonists has been obtained in fewer studies (Igawa et al 1999;Otsuka et al 2008a;) and the evidence has remained equivocal (Biers et al 2006;Frazier et al 2011). Nevertheless, β3-ARs have become an attractive target for novel drugs for the treatment of patients suffering from the overactive bladder syndrome.…”

Somatic Comorbidity in Women with Overactive Bladder Syndrome

“…18 Although further studies are needed to uncover which environmental exposures constitutes the link between asthma and overactive bladder it is noteworthy that β3-agonists, initially intended for the treatment of asthma, are prescribed for the treatment of overactive bladder. 19, 20 …”

The Overactive Bladder: New Concepts of Etiology and Treatment

“…Novel Therapies β3-Adrenoceptor stimulation causes bladder relaxation and is therefore being evaluated as a possible treatment of OAB. The β3 agonist AJ-9677 promotes bladder relaxation in rat, monkey and human detrusor tissue in vitro [68]. An evaluation in rats showed that intravesical administration of two different β3 agonists promoted bladder relaxation [69].…”