Pharmacological Characterization of a New Antimuscarinic Agent, Solifenacin Succinate, in Comparison with Other Antimuscarinic Agents

Abstract

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...

Are Antimuscarinic Drugs Effective Against Urinary Frequency Mediated by Atropine-Resistant Contractions?

“…Thus, propiverine was confirmed as a drug capable of improving urinary frequency at clinical dose levels both via its antimuscarinic effect and its effect of inhibiting Ca 2+ influx into the urinary bladder myocytes. A more than 100-fold difference was observed in the binding affinity of tolterodine and solifenacin between the M 3 muscarinic receptors and the PAA sensitive L-type Ca 2+ channels (24), which was inferred to be the reason why effect of these drugs in ameliorating urinary frequency was inadequate at the doses used in this study. The efficacy of administering solifenacin at 100 mg/kg and tolterodine at 30 mg/kg was investigated in a preliminary study; however, the increase in amount of the micturition weight decreased.…”

“…Among the anticholinergic drugs, the Ki value of propiverine for the PAA sensitive L-type Ca 2+ channels was 4.6-fold higher than for the M 3 muscarinic receptor (24), which is thought to be the reason for the close ED 50 values obtained between the ACh-induced frequency model and CaCl 2 -induced frequency model. Thus, propiverine was confirmed as a drug capable of improving urinary frequency at clinical dose levels both via its antimuscarinic effect and its effect of inhibiting Ca 2+ influx into the urinary bladder myocytes.…”

Clinical effects of solifenacin succinate combined with other drugs in treating overactive bladder after transurethral resection of the prostate

“…The bladder and prostatic smooth muscle were important in human urinary system, under normal physiological status, the cholinergic receptor and adrenal gland could effectively control their contraction and relaxation, M choline receptor and α1 receptor could act on prostate and bladder detrusor to result in normal extraction [6,7], and act on the trigone of urinary bladder and urethral sphincter to result in relaxation [8,9]. In clinic, the anticholinergic agents were universally and widely applied, in human's some tissues and organs like salivary gland and gastric and intestinal smooth muscle, M3 receptors were widely distributed.…”

Effects of solifenacin in patients with neurogenic detrusor overactivity as a result of spinal cord lesion

“…4,6,8 Solifenacin is a once daily oral antimuscarinic drug with a high affinity for the M 3 muscarinic receptor in the bladder, which is regarded to be the main mediator of detrusor contractility. 9 Solifenacin has been reported to be more effective (quality of life, patient reported cure, incontinence and urgency episodes) and cause fewer adverse events and thus fewer withdrawals than other antimuscarinic drugs in patients with idiopathic overactive bladder. 10 To date, there is no data on the efficacy of solifenacin in the treatment of NDO as a result of SCI.…”