Effects of antiarrhythmic drugs on canine ventricular arrhythmia models: Which electrophysiological characteristics of drugs are related to their effectiveness?

Abstract

In order to compare and clarify the effects of various antiarrhythmic drugs when given as monotherapy, we reevaluated our previous data on antiarrhythmic drugs and recalculated antiarrhythmic plasma concentrations of drugs for several canine arrhythmia models. We used three spontaneously occurring arrhythmias: a) digitalis-, b) two-stage coronary ligation-, and c) adrenaline-induced arrhythmias. All antiarrhythmic drugs of class I suppressed digitalis arrhythmia, and, except for lidocaine, also suppressed coronary ligation arrhythmia. Class II antiarrhythmic drugs, beta blockers, and class IV antiarrhythmic drugs, Ca antagonists, had common features of effectiveness and suppressed adrenaline arrhythmia in relatively low concentrations. Class III drugs were not effective on these three arrhythmias. Differences among the antiarrhythmic effects of class I drugs could not be explained by their subclassification based either on action potential duration or kinetic properties of dissociation or association with Na channels. New triggered arrhythmia models in vivo and in vitro canine hearts were developed, and drug effects were not the same as those on the three spontaneously occurring arrhythmia models.

Effects of OPC-18790, a New Positive Inotropic Agent, on Canine Ventricular Arrhythmias

“…OPC-18790 had no deleterious effect on the digitalis VT, and it is consistent with our previous proposal that the occurrence of digitalis VT is not influenced by the Ca channel activities (11,13). The practical importance of this result is that this new positive inotropic agent can be used in combination with digitalis without increasing the risk of arrhythmia, and this is a common observation among new positive inotropic drugs in our previous study (6).…”

“…Our previous experiments using three VT models showed that coronary ligation-induced and digitalis-induced VTs are Na channel-dependent, because they are suppressed by class I antiarrhythmic drugs, while adrenaline VT is Ca channel-dependent, because it is suppressed by class II 8-blockers and class IV Ca channel blockers (13). Like other new positive inotropic agents (6, 7), which are phos phodiesterase inhibitors and increase cardiac Ca current, OPC-18790 was shown to aggravate adrenaline VTs.…”

Utilization of an Isolated, Blood-Perfused Canine Papillary Muscle Preparation as a Model to Assess Efficacy and Adversity of Class I Antiarrhythmic Drugs

“…We have previously described the use of the classical digitalis-induced and coronary ligation-induced arrhyth mia models to assess the antiarrhythmic activity of class I drugs (11). Correlation between EDSO(IVCT) in this study and antiarrhythmic effects on the in vivo canine digitalis arrhythmia of class I drugs expressed by the anti arrhythmic IC50 plasma concentrations from our earlier reports (11) is shown in Fig.…”

“…Other drugs were tested at 500-msec driving interval. An tiarrhythmic plasma concentrations were calculated from our earlier reports (11,39,40). P: procainamide, D: disopyramide, L4: lido caine at 400-msec driving interval, L3: lidocaine at 300-msec driving interval, M4: mexiletine at 400-msec driving interval, M3: mexiletine at 300-msec driving interval, F: flecainide, ME: ME3202, AN: AN 132.…”

“…Correlation between cardiac direct effects and antiar rhythmic activity: We examined the correlation between the intraarterial ED50 doses in this study and the antiar rhythmic IC50 plasma concentrations obtained in our previous canine arrhythmia model studies, namely digi talis and coronary ligation-induced arrhythmias (11,39,40). Although these arrhythmias most likely are caused by triggered activity from delayed after depolarizations, ab normal automaticity and/or re-entrant excitation in very depolarized tissues (11,39,40), a good correlation was found only between EDSO(IVCT) in this current study and IC50 of two different types of arrhythmia models.…”