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The electrophysiological and antiarrhythmic actions of tedisamil, lidocaine, and various combinations of tedisimal and lidocaine mixtures against ischaemia-induced arrhythmias in rats Sarraf, Guilda

Abstract

Sudden cardiac death due to ischaemia-induced ventricular arrhythmias is the leading cause of death worldwide. Today, we have not yet developed a drug that is ideal in suppressing ischaemia-induced arrhythmias. The best drug used clinically is amiodarone. This is an antiarrhythmic with class I, II, III, and IV activities. This multi-antiarrhythmic activity of amiodarone makes this drug pharmacologically complex. However, it also suggests that drug combinations could produce a better antiarrhythmic than single drugs. Researchers have used this hypothesis to study different drug mixtures such as quinidine plus mexiletine. Duff et al. (1986 and 1990), have suggested possible synergistic interaction between quinidine (a class la) and mexiletine (a class lb) drug. However, other researchers, including Nortran Pharmaceuticals (in Vancouver) are trying to develop new antiarrhythmics which have both class lb and class III activity. Their proposal is based on the prediction of the modulated receptor hypothesis which states that combinations of class lb and class III drugs could act synergistically to produce a better antiarrhythmic protection than either drug alone. This is based on the possibility that a greater prolongation of the effective refractory period can be produced when an action potential prolonging drug (ie, class III) and an inactive-state sodium channel blocker (ie, class lb) are mixed. Mixture of class lb plus class III could provide a better antiarrhythmic than class la plus class lb because a class III drug can produce a greater prolongation of the action potential duration, thus allowing for a greater block of inactive-state sodium channels by class lb drug. In the present study, we chose tedisamil (a class III agent) and lidocaine (a class lb agent) to study the mechanistic interaction between a class III and lb drug which have been shown by Nortran Pharmaceuticals to have superior antiarrhythmic protection compared to each drug alone. Rat models were used to induce ischaemia-induced arrhythmias by occlusion of their left main coronary artery. Tedisamil alone, lidocaine alone, and various combinations of tedisamil and lidocaine were studied for their electrophysiological and antiarrhythmic effects. The results support a possible synergistic interaction between tedisamil and lidocaine. This is because tedisamil produced a leftward shift in the antiarrhythmic dose-response curve of lidocaine alone, and vice-versa. As well, the isobologram showed that the combination of tedisamil and lidocaine produced an ED₅₀ antiarrhythmic isobologram which lay below the line of additivity. Although this was not statistically significant, it still suggests that tedisamil and lidocaine have at least an additive interaction, and possibly a synergistic interaction. Interestingly, 2 μmole/kg/min tedisamil plus 2 μmole/kg/min lidocaine produced the best antiarrhythmic protection because the antiarrhythmic ED5 0 was furthest below the line of additivity in the isobologram. This combination synergistically reduced the arrhythmia score and ventricular tachycardia, as well as completely abolishing ventricular fibrillation. In summary, this thesis supports the prediction of modulated receptor hypothesis that class lb plus class III combination can produce a better antiarrhythmic protection than either drug alone.

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