Urinary bladder smooth muscle is innervated by both sympathetic and parasympathetic nerves. Acetylcholine released from postganglionic parasympathetic nerve terminals activates postjunctional muscarinic receptors in urinary bladder, which modulate urinary bladder contraction during the voiding phase and control detrusor tone during the filling phase. Five muscarinic receptor subtypes (M 1 -M 5 ) have been identified by both molecular biological and pharmacological investigations.1) The urinary bladder smooth muscle contains a mixed population of muscarinic M 2 and M 3 receptors.2) Although muscarinic M 2 receptors are numerically predominant, muscarinic M 3 receptors are considered to predominate in the mediation of bladder contraction.3,4) An important functional role of the muscarinic M 3 receptor in mediating bladder contraction has also been suggested in experiments using mutant mice lacking the muscarinic M 3 receptor gene.
5)Overactive bladder is characterized by symptoms of urgency and urinary frequency with or without urge incontinence. It has a profoundly negative effect on the quality of life of those affected. Muscarinic receptor antagonists are the most widely used therapy for overactive bladder.6-8) Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. Affinity constants (K i values) of this drug for human muscarinic M 1 , M 2 and M 3 receptors only have been reported, along with its antagonism of the contractile effect of carbachol in isolated guinea pig urinary bladder.9) The present study was therefore undertaken to investigate the affinity of solifenacin for all human muscarinic receptor subtypes (M 1 -M 5 ) and its functional muscarinic M 3 receptor antagonism in rats, and to compare the results with those for tolterodine, oxybutynin, darifenacin, propiverine and atropine. Additionally, we also investigated the effect of solifenacin on voiding function in anesthetized rats.
MATERIALS AND METHODS
MaterialsSolifenacin succinate (YM905, Vesicare ® ), tolterodine tartrate, darifenacin and propiverine hydrochloride were prepared by Astellas Pharma Inc. (Tokyo, Japan). Oxybutynin chloride, atropine sulfate and carbachol (carbamylcholine chloride) were purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Darifenacin was dissolved in dimethyl sulfoxide and the others were dissolved in dimethyl sulfoxide, Krebs-Henseleit solution or physiological saline.Animals Male Wistar rats and male Sprague-Dawley rats were purchased from Charles River Laboratories Japan (Kanagawa, Japan) and Japan SLC (Shizuoka, Japan), respectively. In in vitro studies, rats were sacrificed by exsanguination under ether anesthesia. All animal experiments were performed in compliance with the regulations of the Institutional Animal Ethical Committee of Astellas Pharma Inc.Radioligand Receptor Binding Assay Membranes of Chinese hamster ovary (CHO)-K1 cells expressi...
Bladder over distention/emptying induced bladder blood flow decrease/partial recovery and caused bladder overactivity via a mechanism other than capsaicin sensitive C-fiber activation. Findings in tamsulosin treated rats confirmed the potency of tamsulosin to increase bladder blood flow and ameliorate bladder overactivity.
To investigate the pharmacological properties of mirabegron in in vitro and in vivo, the effects on cAMP accumulation in Chinese hamster ovary (CHO) cells expressing rat β-adrenoceptors, the relaxant activity in isolated rat bladder smooth muscle, and the voiding effects in cerebral infarcted rats were evaluated. Mirabegron increased cAMP accumulation with EC(50) value and intrinsic activity of 19 nmol/L and 1.0, respectively, in CHO cells expressing rat β(3)-adrenoceptors. The EC(50) values and the intrinsic activities of mirabegron were 610 nmol/L and 0.6 for rat β(1)-adrenoceptors and were sumless and 0.1 for β(2)-adrenoceptors, respectively. Mirabegron showed concentration-dependent relaxant and full agonistic effects in rat bladder strips under passive tension with EC(50) value of 290 nmol/L. The concentration-response curve of mirabegron was affected neither by the β(1)-adrenoceptor selective antagonist CGP-20712A nor by the β(2)-adrenoceptor selective antagonist ICI-118,551. In in vivo studies with cerebral infarcted rats, a significant decrease in the volume voided per micturition compared with sham-operated rats was observed. Mirabegron dose-dependently increased the volume voided per micturition. In conclusion, we have extended the selectivity profile of mirabegron to rats and demonstrated that it is effective via stimulation of β(3)-adrenoceptors in a rat cerebral infarction model of detrusor overactivity.
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