RSD1019 suppresses ischaemia‐induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits

• Published in: British journal of pharmacology Vol. 131; no. 3; pp. 405 - 414
• Main Authors: Barrett, Terrance D, MacLeod, Bernard A, Walker, Michael J A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2000; Nature Publishing
• Subjects: Action Potentials - drug effects; Animals; Anti-Arrhythmia Agents - pharmacology; Anti-Arrhythmia Agents - therapeutic use; antiarrhythmic drugs; Antiarythmic agents; antifibrillatory; Arrhythmias; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - prevention & control; Biological and medical sciences; Blood Pressure - drug effects; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cardiovascular system; Cyclopropanes - pharmacology; Electrocardiography - drug effects; Electrophysiology; Heart Rate - drug effects; ischaemia‐selective; Ischemia - physiopathology; Lidocaine - pharmacology; Male; Medical sciences; monophasic action potentials; Morpholines; myocardial ischaemia; Pharmacology. Drug treatments; Rabbits; ventricular fibrillation; Intravenous administration; Arrhythmia; Tedisamil; Rabbit; Cardiovascular disease; Action potential; Myocardial disease; Ventricular fibrillation; Dose activity relation; Vascular disease; Ischemia; Heart disease; Lagomorpha; Antiarrhythmic agent; Coronary heart disease; Excitability disorder; Biological activity; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Myocardium; Organic amide; Circulatory system; Hemodynamics; Lidocaine; Comparative study
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703592

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 μmol 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 μmol kg−1 min−1 i.v., prolonged MAP duration at 90% repolarization (MAPD90%) 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 μmol kg−1 min−1 i.v., produced a small increase in MAPD90% 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. British Journal of Pharmacology (2000) 131, 405–414; doi:10.1038/sj.bjp.0703592