Solifenacin is an antimuscarinic agent used to treat symptoms of overactive bladder. Pharmacologically significant amounts of solifenacin were excreted in the urine of humans taking a clinical dose of this drug. The aim of this study is to measure muscarinic receptor binding in the bladder urothelium and detrusor muscles of rats following the intravesical instillation of solifenacin. Muscarinic receptors were measured by radioreceptor assay using [N-methyl- Key words solifenacin; bladder urothelium; muscarinic receptor binding; intravesical administrationAn overactive bladder is characterized by symptoms of urgency and urinary frequency with or without urge incontinence. The condition has a detrimental effect on physiological functioning and psychological well-being and quality of life. 1,2) Antimuscarinic agents are widely used to treat overactive bladder since parasympathetic innervation is the predominant stimulus for bladder contraction.3,4) However, their use is associated with the anticholinergic side effects; dry mouth, constipation, somnolence, blurred vision and cognitive impairment, suggesting the importance of bladder selectivity.Solifenacin succinate is a muscarinic receptor antagonist intended for the treatment of symptoms of overactive bladder. 5,6) The inhibitory effect of solifenacin on carbachol-stimulated Ca 2+ mobilization is equipotent with oxybutynin in detrusor cells, but 2 to 10 times weaker in salivary gland cells. [5][6][7] In vivo studies in anesthetized rats have shown that solifenacin is 4-7 times more potent in inhibiting bladder contraction than salivation, 5,7) thereby indicating bladder selectivity. The bladder urothelium is a multifunctional tissue that acts as a barrier between the vesical contents of the lower urinary tract and the underlying tissues and as a sensory organ by transducing physical and chemical stresses to the associated afferent nervous system and underlying smooth muscle. Muscarinic receptor subtypes are detected in the bladder urothelium of humans. [8][9][10] The bladder urothelium was shown to respond to stretch and muscarinic agonist stimulation by releasing mediators such as adenosine triphosphate (ATP), nitric oxide (NO) and acetylcholine (ACh) itself, which may modulate afferent activity through nerve and/or myofibroblasts. 11-13)Therefore, urothelial muscarinic receptors could be a site of action for the antimuscarinic agents used to treat overactive bladder.We have previously shown that solifenacin compared with oxybutynin binds muscarinic receptors persistently in the mouse bladder after oral administration.14) Kim et al. showed that intravesically infused antimuscarinic agents suppressed the carbachol-induced bladder overactivity.15) When administered orally, a pharmacologically significant amount of solifenacin was suggested to be excreted in the urine of humans taking clinical dose (5-10 mg) of this agent.16) Solifenacin succinate has approximately 15% active compound excreted into the urine compared with 3% and less than 1% with darifenacin and to...
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