title: Ethacizin blockade of calcium channels: a test of the guarded receptor hypothesis.
abstract: The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolated frog ventricular cells using the whole cell voltage-clamp methodology. Ethacizin was found to block inward calcium current in a frequency-, voltage-, and concentration-dependent manner. The frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of calcium channels harboring either an accessible or an inaccessible binding site. With repetitive stimulation, the pulse-to-pulse reduction in peak current is shown to be exponential, with a rate linearly related to the interstimulus interval and the drug concentration. Observed frequency- and concentration-dependent blocks were consistent with the predictions of the model, and mixture-specific rate constants were estimated from these data. The negligible shift in channel inactivation and the reduction of apparent binding and unbinding rates with more polarized membrane potentials imply the active moiety of ethacizin blocks open channels and is trapped within the channel at resting membrane potentials. The binding rate at 0 mV is similar to that observed in studies of interactions of other open channel blocking agents with voltage- and ligand-gated channels.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: C F
authors.initials: CF
authors.lastname: Starmer
authors.forename: A I
authors.initials: AI
authors.lastname: Undrovinas
authors.forename: F
authors.initials: F
authors.lastname: Scamps
authors.forename: G
authors.initials: G
authors.lastname: Vassort
authors.forename: V V
authors.initials: VV
authors.lastname: Nesterenko
authors.forename: L V
authors.initials: LV
authors.lastname: Rosenshtraukh
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation; D004594:Electrophysiology; D006352:Heart Ventricles; D008955:Models, Cardiovascular; D016293:Moricizine / Q000031:analogs & derivatives*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010640:Phenothiazines / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010640:Phenothiazines; C027240:diethylamino-ethmozine; D016293:Moricizine