Binding activities by propiverine and its N-oxide metabolites of L-type calcium channel antagonist receptors in the rat bladder and brain.

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.