title: RSD1019 suppresses ischaemia-induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits.
abstract: The electrophysiological actions of lidocaine, tedisamil and RSD1019 were assessed on normal and ischaemic cardiac tissue using monophasic action potentials (MAPs) recorded from the epicardium of anaesthetized rabbits. Drug effects on ischaemia-induced arrhythmias were assessed simultaneously in the same rabbits. Lidocaine, infused at 2.5, 5 and 10 micromol kg(-1) min(-1) i.v., accelerated and worsened the electrophysiological derangement caused by ischaemia, had profibrillatory actions and reduced the time to the occurrence of ventricular fibrillation (VF) relative to controls. Tedisamil, infused at 0.063, 0.125 and 0.25 micromol kg(-1) min(-1) i.v., prolonged MAP duration at 90% repolarization (MAPD(90%)) before induction of ischaemia in a dose-related manner; however, this effect was not maintained 5 min after induction of ischaemia. Tedisamil had no significant antiarrhythmic actions over the dose-range tested. RSD1019, infused at 2, 4 and 8 micromol kg(-1) min(-1) i.v., produced a small increase in MAPD(90%) before induction of ischaemia and only at the highest dose tested. In contrast to tedisamil, RSD1019 suppressed ischaemia-induced MAP shortening assessed 5 min after induction of ischaemia. This effect was dose-related. RSD1019 completely prevented ischaemia-induced tachyarrhythmias at the mid and highest infusion levels tested. The results of this study illustrate a pathologically targeted approach for preventing ischaemia-induced arrhythmias. Suppression of ischaemia-induced MAP shortening, demonstrated herein for RSD1019, represents a novel antifibrillatory approach.
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Vancouver, B.C., V6T 1Z3, Canada.
authors.forename: T D
authors.initials: TD
authors.lastname: Barrett
authors.forename: B A
authors.initials: BA
authors.lastname: MacLeod
authors.forename: M J
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006339:Heart Rate / Q000187:drug effects; D007511:Ischemia / Q000503:physiopathology*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009025:Morpholines; D011817:Rabbits
chemical_list: D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D009025:Morpholines; C419875:RSD 1019; D008012:Lidocaine; C059921:tedisamil