Use-dependent blockade of cardiac pacemaker current (If) by cilobradine and zatebradine.
The action of the bradycardiac agents, cilobradine (DK-AH269) and zatebradine (UL-FS49), on the cardiac pacemaker current (If) was investigated on short Purkinje fibres from sheep hearts, using the two-microelectrode voltage-clamp technique, and on isolated rabbit sino-atrial cells with the patch clamp technique. These drugs reduce dose dependently the amplitude of the If, without modifying either the voltage dependence or the kinetics of channel activation. When voltage-clamp pulse trains were applied, cilobradine induced a use-dependent blockade of If that was stronger and faster than that with zatebradine. Recovery from blockade during prolonged hyperpolarization was significantly faster with zatebradine. Presumably, both drugs block the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel by gaining access to a binding site within the open channel pore, and are removed from the blocking site by strong hyperpolarization with large inward If through the open channel. Cilobradine, compared to zatebradine blocks If more effectively and faster in both preparations. Consequently cilobradine strongly reduces the pacemaker diastolic depolarization rate and the cell's firing frequency.
Laboratory for Electrophysiology, Department of Physiology, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020 Antwerp, Belgium. ppvbog@ruca.ua.ac.be
Pierre Paul
PP
Van Bogaert
François
F
Pittoors
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001683:Biological Clocks / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000187:drug effects; D012756:Sheep; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects; D013237:Stereoisomerism
D001552:Benzazepines; D002316:Cardiotonic Agents; C087873:DK-AH 268; C043636:zatebradine