Pharmacological Effects of KRP-197 on the Human Isolated Urinary Bladder

Abstract

KRP-197, 4-(2-methylimidazol-l-yl)-2,2-diphenylbutyramide, is a newly synthesized antimuscarinic drug, developed for the treatment for overactive bladder. For evaluation of pharmacological characteristics of KRP-197, we investigated whether it influenced both prejunctional and postjunctional muscarinic receptors on the isolated human detrusor smooth muscles as compared with the effects of atropine, oxybutynin, and propiverine. Using the muscle bath technique, we investigated the effects of various antimuscarinic drugs on the contractions induced by carbachol, KCl, CaCl₂, and electrical field stimulation. Furthermore, using high-performance liquid chromatography with a microdialysis technique, we measured the acetylcholine release from the muscle strips during electrical field stimulation. The effects of various antimuscarinic drugs on acetylcholine releases were also evaluated. Pretreatment with various antimuscarinic drugs caused parallel shifts to the right in carbachol-induced concentration-response curves. The rank order of pA₂ values was KRP-197 ≧ atropine > oxybutynin > propiverine. Atropine and KRP-197 did not cause significant inhibition of KCl- and CaCl₂-induced contractions. All drugs caused concentration-dependent inhibitions in electrical field stimulation-induced contractions. Pretreatment with atropine and propiverine did not cause significant changes in electrical field stimulation-induced acetylcholine release. However, KRP-197, and oxybutynin caused significant decreases in acetylcholine release. The present study demonstrates that KRP-197 has an inhibitory effect on postjunctional muscarinic receptors as well as on prejunctional muscarinic receptors to modulate acetylcholine release in human detrusor smooth muscles. The findings suggest the usefulness of KRP-197 as a therapeutic drug for an overactive bladder with symptoms of frequency, urgency, and urge incontinence.

Pharmacological Effects of Solifenacin on Human Isolated Urinary Bladder

“…These data about oxybutynin and propiverine are consistent with previous reports of significant Ca 2+ -channelantagonistic action [19,20,23,24,26,27] . channel-antagonistic action, but the effects of solifenacin on KCl-and CaCl 2 -induced contractions were lower than those of oxybutynin and propiverine.…”

“…In the acetylcholine release experiment, the microdialysis methods for the smooth muscle strips were performed as previously described [21,22,25,26] . The dialysis probe (O-P-100-10; Eicom, Kyoto, Japan) was a 0.22 !…”

“…Acetylcholine determination was performed by a combination of high-performance liquid chromatography, enzyme reaction, electrochemical detection, as previously described [21,22,25,26] . In brief, a solution that consisted 0.1 mmol/l Na 2 HPO 4 (pH 8.5), containing 300 mg/l sodium 1-decanesulfonate and 65 mg/l tetramethylammonium chloride, was delivered as the mobile phase at a rate of 0.6 ml/min.…”

Selective Binding of Bladder Muscarinic Receptors in Relation to the Pharmacokinetics of a Novel Antimuscarinic Agent, Imidafenacin, to Treat Overactive Bladder

“…It has been reported to have high affinity for M 3 receptors, which play an important role in bladder contraction, to exhibit functional selectivity toward the bladder over the salivary gland and to have little pharmacological effect on the CNS even at high doses (Kobayashi et al, 2007a,b). Murakami et al (2003) showed that imidafenacin exerted an inhibitory effect on postjunctional muscarinic receptors as well as prejunctional muscarinic receptors to modulate the release of acetylcholine in human detrusor smooth muscles. Thus, imidafenacin may select the bladder over the salivary gland, reducing the risk of side effects on the CNS in the treatment of overactive bladders.…”

Absorption, Metabolism, and Excretion of [14C]Imidafenacin, a New Compound for Treatment of Overactive Bladder, After Oral Administration to Healthy Male Subjects

“…Imidafenacin showed high in vitro affinity for muscarinic receptor subtypes M 1 and M 3 in the functional assay using isolated animal tissues and in the binding assay using recombinant human receptors (Miyachi et al, 1999;Kobayashi et al, 2007a). In addition, imidafenacin inhibited carbachol-induced contraction of isolated guinea pig and human bladder mediated by the M 3 receptor and acetylcholine release from isolated rat and human bladder mediated by the prejunctional M 1 receptor (Murakami et al, 2003;Kobayashi et al, 2007a). A carbachol-induced reduction in bladder capacity and distention-induced rhythmic bladder contraction were prevented by imidafenacin dose dependently in conscious rats (Miyachi et al, 1999;Kobayashi et al, 2007b).…”