title: Effects of thienopyridines and thienopyrimidinones on L-type calcium current in isolated cardiomyocytes.
abstract: Thienopyridines (ticlopidine, clopidogrel) are frequently used drugs in antiplatelet therapy and have been shown to exert a more pronounced negative inotropic effect than thienopyrimidinones. We hypothesized that these differences are due to a differential impact of thienopyridines and thienopyrimidinones on L-type calcium current at the single-cell level. The effects of thienopyridines and thienopyrimidinones were studied on L-type calcium current and action potential parameters with the whole-cell patch-clamp technique in isolated myocytes from guinea pig ventricle and human atrial appendage. Ticlopidine showed the greatest impact on the L-type calcium current in guinea pig myocytes. It significantly reduced L-type calcium current density as well as shifted half maximal inactivation potential to more negative potentials compared to clopidogrel (at 30 μmol/L) and to all thienopyrimidinones (30 and 100 μmol/L). Clopidogrel significantly reduced the L-type calcium current density as well as shifted the half maximal inactivation potential to more negative potentials compared to all thienopyrimidinones at 100 μmol/L only. In contrast, thienopyrimidinones did not affect L-type calcium current properties. The significant different effects of thienopyridines and thienopyrimidinones could also be demonstrated in human atrial myocytes. The more pronounced negative inotropic effect of thienopyridines is well explained by our results demonstrating a differential impairment of L-type calcium current by thienopyridines and thienopyrimidinones. L-type calcium current impairment by thienopyridines may be of special relevance for patients with cardiac diseases characterized by ionic remodelling.
authors.affiliation: Institute of Biophysics, Center of Physiological Medicine, Medical University Graz, Harrachgasse 21/4, 8010, Graz, Austria. brigitte.pelzmann@medunigraz.at
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pelzmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Zorn-Pauly
authors.forename: Seth
authors.initials: S
authors.lastname: Hallström
authors.forename: Heinrich
authors.initials: H
authors.lastname: Mächler
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jakubowski
authors.forename: Petra
authors.initials: P
authors.lastname: Lang
authors.forename: Bernd
authors.initials: B
authors.lastname: Koidl
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D020517:Atrial Appendage / Q000166:cytology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002478:Cells, Cultured; D000077144:Clopidogrel; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D058924:Thienopyridines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D010975:Platelet Aggregation Inhibitors; D011743:Pyrimidines; D058924:Thienopyridines; D013876:Thiophenes; D000077144:Clopidogrel; D013988:Ticlopidine