title: Binding activities by propiverine and its N-oxide metabolites of L-type calcium channel antagonist receptors in the rat bladder and brain.
abstract: The present study was undertaken to characterize the binding activities of propiverine and its N-oxide metabolites (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide: P-4(N-->O), 1-methyl-4-piperidyl benzilate N-oxide: DPr-P-4(N-->O)) toward L-type calcium channel antagonist receptors in the rat bladder and brain. Propiverine and P-4(N-->O) inhibited specific (+)-[(3)H]PN 200-110 binding in the rat bladder in a concentration-dependent manner. Compared with that for propiverine, the K(i) value for P-4(N-->O) in the bladder was significantly greater. Scatchard analysis has revealed that propiverine increased significantly K(d) values for bladder (+)-[(3)H]PN 200-110 binding. DPr-P-4(N-->O) had little inhibitory effects on the bladder (+)-[(3)H]PN 200-110 binding. Oxybutynin and N-desethyl-oxybutynin (DEOB) also inhibited specific (+)-[(3)H]PN 200-110 binding in the rat bladder. Propiverine, oxybutynin and their metabolites inhibited specific [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the rat bladder. The ratios of K(i) values for (+)-[(3)H]PN 200-110 to [(3)H]NMS were markedly smaller for propiverine and P-4(N-->O) than oxybutynin and DEOB. Propiverine and P-4(N-->O) inhibited specific binding of (+)-[(3)H]PN 200-110, [(3)H]diltiazem and [(3)H]verapamil in the rat cerebral cortex in a concentration-dependent manner. The K(i) values of propiverine and P-4(N-->O) for [(3)H]diltiazem were significantly smaller than those for (+)-[(3)H]PN 200-110 and [(3)H]verapamil. Further, their K(i) values for [(3)H]verapamil were significantly smaller than those for (+)-[(3)H]PN 200-110. The K(i) values of propiverine for each radioligand in the cerebral cortex were significantly (P<0.05) smaller than those of P-4(N-->O). In conclusion, the present study has shown that propiverine and P-4(N-->O) exert a significant binding activity of L-type calcium channel antagonist receptors in the bladder and these effects may be pharmacologically relevant in the treatment of overactive bladder after oral administration of propiverine.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Center of Excellence Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka Taiho Pharmaceutical Co LTD, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Uchida
authors.forename: Souhei
authors.initials: S
authors.lastname: Kurosawa
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujino Oki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kato
authors.forename: Masato
authors.initials: M
authors.lastname: Nanri
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001561:Benzilates / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004110:Diltiazem / Q000378:metabolism; D017275:Isradipine / Q000378:metabolism; D008297:Male; D008333:Mandelic Acids / Q000378:metabolism; D019832:N-Methylscopolamine / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium; D001743:Urinary Bladder / Q000378:metabolism*; D014700:Verapamil / Q000378:metabolism
chemical_list: D001561:Benzilates; D020746:Calcium Channels, L-Type; D008333:Mandelic Acids; D014316:Tritium; C015586:propiverine; C032681:desethyloxybutynin; D014700:Verapamil; D004110:Diltiazem; C005419:oxybutynin; D019832:N-Methylscopolamine; D017275:Isradipine