Relationship between ischaemia-selective drug action and antiarrhythmic efficacy

• Main Author: Barrett, Terrance Donald
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/9817

This thesis explores the relationship between the electrophysiological actions of drugs on ischaemic myocardial tissue and their effects on arrhythmias induced by ischaemia. Our hypothesis was that drugs with ischaemia-selective electrophysiological actions would provide better antiarrhythmic protection in the setting of acute myocardial ischaemia than those which lacked such selectivity. The actions of a selection of standard antiarrhythmic drugs (quinidine, lidocaine, flecainide and tedisamil) were compared to those of the novel drug RSD1019, under conditions designed to mimic, or produce, myocardial ischaemia in rat hearts. In support of the hypothesis, drugs which exhibited selectivity for the conditions of myocardial ischaemia (i.e., lidocaine and RSD1019) suppressed ischaemia-induced arrhythmias effectively. Drugs that were more potent in normal myocardial tissue, and which lacked such selectivity (i.e., quinidine, flecainide and tedisamil), were less effective for suppression of ischaemia-induced arrhythmias. Further studies were carried out in order to evaluate the hypothesis using monophasic action potential (MAP) recordings from the epicardium of anaesthetised rabbits before and after induction of myocardial ischaemia. The advantage offered by this preparation was that it allowed the electrophysiological changes caused by ischaemia, and drug effects thereon, to be assessed simultaneously with arrhythmias resulting from myocardial ischaemia. In this preparation, both RSD1019 and lidocaine influenced the electrophysiological properties of ischaemic tissue and arrhythmias but in different ways. Lidocaine exacerbated the electrophysiological derangement caused by ischaemia and had proarrhythmic actions. RSD1019 prevented MAP shortening caused by ischaemia and arrhythmias. In contrast to RSD1019, the IK(ATP> blocker glibenclamide failed to prevent MAP shortening caused by ischaemia and the antiarrhythmic effects produced by this drug are unlikely to be related to its effects on ischaemic myocardial tissue. In summary, ischaemia-selective drug actions have the same potential benefits and risks associated with drug action in normal myocardial tissue. The action of a drug on ischaemic tissue can be pro- or antiarrhythmic depending on the nature of the drug's action and other factors that remain to be identified. Prolongation of action potential duration in ischaemic tissue, demonstrated herein for RSD1019, was associated with antiarrhythmic actions. This mechanism represents a novel approach to suppression of ischaemia-induced arrhythmias.