title: KC8851, a tedisamil analogue with mixed channel blockade, exhibits antiarrhythmic properties against ischemia- and electrically-induced arrhythmias.
abstract: KC8851, a structural analogue of tedisamil, has previously been found to exhibit mixed blockade of K+ and Na+ currents in isolated rat ventricular myocytes. We have now investigated the antiarrhythmic actions of this compound in the anaesthetized rat and isolated rat heart. In the rat, KC8851, at concentrations as low as 0.2 micromol kg(-1) min(-1), widened the QT intervals of the ECG and prolonged the effective refractory period in a dose-dependent manner. Such actions were consistent with blockade of repolarizing K+ currents. At relatively higher doses (above 0.5 micromol kg(-1) min(-1)), KC8851 increased RSh amplitude suggesting blockade of Na+ currents. The compound was found to be effective against occlusion-induced arrhythmias at doses of 0.5 to 2 micromol kg(-1) min(-1). In isolated hearts, the effects of KC8851 on PR and QRS intervals were potentiated by elevated concentrations of K+ and H+. Overall, KC8851 was found to exhibit antiarrhythmic actions consistent with inhibition of both K+ and Na+ currents.
authors.affiliation: Dept. of Pharmacology & Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Abraham
authors.forename: J G
authors.initials: JG
authors.lastname: McLarnon
authors.forename: M J
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000627:therapeutic use*; D004558:Electric Stimulation; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D015221:Potassium Channels; D015222:Sodium Channels; C106999:KC 8851; C059921:tedisamil