title: Pharmacodynamics of propiverine and three of its main metabolites on detrusor contraction.
abstract: 1. Besides its antimuscarinic effects, propiverine may possess an additional mode of action. We compared the effects of propiverine, three of its metabolites (M-5, M-6, M-14) and atropine in human, pig and mouse urinary bladder preparations in order to elucidate the nature of a possible additional mode of action. 2. Like the parent compound, M-5, M-6 and M-14 reduced to variable degrees the contractions elicited by electric field stimulation (EFS) of isolated, urothelium-denuded detrusor strips. In mouse the atropine-resistant and therefore the nonadrenergic, noncholinergic component of contractile response to EFS was reduced by M-5, M-14 and propiverine, but was hardly affected by M-6. 3. Atropine, propiverine and M-6 significantly shifted the cumulative concentration-response curves for carbachol (CCh) to higher concentrations. Atropine and M-6 did not affect the maximum tension induced by CCh. Propiverine, M-5 and M-14 reduced the maximum CCh effect, suggesting at least one additional mode of action. This pattern of response was observed in all the three species, albeit with some differences in sensitivity to the various agents. 4. In freshly isolated human detrusor smooth muscle cells, propiverine and M-14 inhibited the nifedipine-sensitive L-type calcium current (I(Ca)) in a concentration-dependent manner. In contrast, the effects of M-5 and M-6 on I(Ca) were insignificant in the concentration range examined. 5. The investigated responses to propiverine and its metabolites suggest that impairment of maximum CCh-induced contractions is due to strong effect on I(Ca) and that this may be associated with the presence of the aliphatic side chain.
authors.affiliation: Institute of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany. melinda.wuest@mailbox.tu-dresden.de
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.forename: Juliane
authors.initials: J
authors.lastname: Hecht
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Manfred
authors.initials: M
authors.lastname: Braeter
authors.forename: Christian
authors.initials: C
authors.lastname: Schoeberl
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Hakenberg
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001561:Benzilates / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010277:Parasympathomimetics / Q000494:pharmacology; D013045:Species Specificity; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects
chemical_list: D001561:Benzilates; D020746:Calcium Channels, L-Type; D018721:Muscarinic Agonists; D010277:Parasympathomimetics; C015586:propiverine; D001285:Atropine; D002217:Carbachol