| Summary: | 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.
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