Article date: July 2005
By: Melinda Wuest, Juliane Hecht, Torsten Christ, Manfred Braeter, Christian Schoeberl, Oliver W Hakenberg, Manfred P Wirth, Ursula Ravens in Volume 145, Issue 5, pages 608-619
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.
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.
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.
In freshly isolated human detrusor smooth muscle cells, propiverine and M‐14 inhibited the nifedipine‐sensitive L‐type calcium current (ICa) in a concentration‐dependent manner. In contrast, the effects of M‐5 and M‐6 on ICa were insignificant in the concentration range examined.
The investigated responses to propiverine and its metabolites suggest that impairment of maximum CCh‐induced contractions is due to strong effect on ICa and that this may be associated with the presence of the aliphatic side chain.
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.
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.
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.
In freshly isolated human detrusor smooth muscle cells, propiverine and M‐14 inhibited the nifedipine‐sensitive L‐type calcium current (ICa) in a concentration‐dependent manner. In contrast, the effects of M‐5 and M‐6 on ICa were insignificant in the concentration range examined.
The investigated responses to propiverine and its metabolites suggest that impairment of maximum CCh‐induced contractions is due to strong effect on ICa and that this may be associated with the presence of the aliphatic side chain.
British Journal of Pharmacology (2005) 145, 608–619. doi:10.1038/sj.bjp.0706244
DOI: 10.1038/sj.bjp.0706244
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