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.
We prepared a variety of nickel-aluminum complex hydroxides, investigated their physicochemical properties, and evaluated their ability to adsorb phosphate ions (the molar ratios of nickel to aluminum, 1:2, 1:1, 2:1, 3:1, and 4:1, are referred to as NA12, NA11, NA21, NA31, and NA41). NA12 and NA11 have amorphous structures; their specific surface areas and the concentration of associated hydroxyl groups were greater than those of other adsorbents. The number of phosphate ions adsorbed onto NA12 and NA11 was greater than that onto other adsorbents. These results indicated that the phosphate ion adsorption is related to the specific surface area and the amount of hydroxyl groups. The adsorption isotherm data, and the effects of contact time and pH on the adsorption were investigated; our results implied that both the Freundlich equation model and the pseudo-second-order kinetic model describe the adsorption of phosphate ions by NA11. We showed that phosphate ions adsorbed onto NA11 can be desorbed by sodium hydroxide solution at different concentrations and that NA11 could be reused for at least three repeated cycles of phosphate ion adsorption and desorption. This study illustrates that NA11 has the potential for practical application as an adsorbent for phosphate ions from wastewater.
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