Antiarrhythmic drugs, designed to prevent or suppress cardiac arrhythmias, may cause the worsening of an arrhythmia already present in a patient or provoke new and qualitatively different arrhythmias. Cardiotoxic effects of antiarrhythmic drugs may be rate-related or due to intoxication, and may lead to serious and potentially lethal ventricular arrhythmias. The goals of my research were (1) to study the mechanisms by which class IC antiarrhythmic drugs cause ventricular arrhythmias and (2) to explain the mechanisms of action of sodium salts in the reversal of class IC cardiotoxicity. / We used flecainide (F) as a prototype of its class to study the mechanism of action of class IC antiarrhythmic agents (AA). Flecainide is a potent sodium channel blocker producing a major effect on conduction velocity and a minor effect on refractoriness. In vitro studies have shown that F causes frequency-dependent reduction of phase 0 upstroke of cardiac action potential (V$ rm sb{max}$) in ventricular tissue. Flecainide, in the physiologic range of heart rates and at clinically relevant concentrations, may produce rate-dependent effects because of its relatively slow binding and unbinding kinetics. / We studied the effects of F in humans during exercise and showed that F produces an enhanced slowing of conduction when heart rate is increased, because of use-dependent sodium channel blockade. We demonstrated that a variety of class I AA produce use-dependent QRS prolongation in man with characteristic kinetics, which are similar to the kinetics of V$ sb{max}$ depression in vitro. We and others have reported proarrhythmic events associated with the rate-related cardiotoxicity of flecainide. Using a canine model of myocardial infarction, we showed the importance of previous myocardial infarction in flecainide-induced proarrhythmia. With epicardial mapping, we identified anisotropic reentry occurred in the mechanism for the ventricular arrhythmias. We reported that reentry occurred in the infarct zone around an arc of conduction block in the transverse direction. / Cardiotoxicity associated with F includes severe conduction slowing and life-threatening ventricular arrhythmias. Sodium salts have been found to reverse the effects caused by some class I antiarrhythmic agents (AA), but the mechanism of action is unknown. Using electrophysiological and biochemical studies, we investigated the role of extracellular sodium concentration ( (Na$ sp+ sb0$)) in modulating F's actions. In order to isolate the role of (Na$ sp+ sb0$), we used a range of (Na$ sp+ sb0$) and equimolar substitution with choline chloride. Our microelectrode experiments showed the ability of (Na$ sp+ sb0$) to modulate directly F's effects on the phase 0 upstroke (V$ rm sb{max}$). Our radioligand studies of displacement of ($ sp3$H) -batrachotoxinin A 20$ alpha$-benzoate ( ($ sp3$H) -BTXB) binding showed that this interaction was due to an effect of (Na$ sp+ sb0$ (on the binding of F to its receptor. We found that EC$ sb{50}$ values for depression of V$ rm sb{max}$ in electrophysiologic experiments and IC$ sb{50}$ values for flecainide displacement of ($ sp3$H) -BTXB in biochemical studies were highly correlated (r = 0.99). A limitation of our electrophysiologic study was the use of V$ rm sb{max}$ as an index of sodium current (I$ rm sb{Na}$). Using the whole-cell voltage clamp technique we found that increasing (Na$ sp+ sb0$) opposed F's blocking effect on I$ rm sb{Na}$, confirming the role of (Na$ sp+ sb0$ (. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.40233 |
| Date | January 1996 |
| Creators | Ranger, Suzanne |
| Contributors | Nattel, Stanley (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001496056, proquestno: NN12465, Theses scanned by UMI/ProQuest. |
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