HEMODYNAMIC-EFFECTS OF ANTIARRHYTHMIC COMPOUNDS - INTRINSIC EFFECTS AND AUTONOMIC MODULATION

Besides their proarrhythmic side-effects, most antiarrhythmic drugs ex ert varying degrees of depressant action on hemodynamics, which may li mit their utility, especially in patients with compromised left ventri cular function. Antiarrhythmic drugs have not only myocardial inotropi c effects but also act on the coronary and peripheral circulation and the heart rate. Thus, sophisticated and appropriate experimental condi tions are necessary to define the effect of their direct negative inot ropic actions versus their circulatory effects and the impact of drug- induced autonomic modulation. This study describes an extended compari son of amiodarone, d-sotalol, d,l-sotalol, and dofetilide as class III antiarrhythmic drugs with the actions of several class I antiarrhythm ic drugs in an open-chest model. The experimental model permits not on ly measurements in the intact circulation but also measurements of iso volumic indexes of contractility, which are independent of drug-induce d changes in ventricular preload and afterload. Furthermore, after aut onomic blockade, hemodynamic effects can be measured independently of modulatory adrenergic effects in such a model, d-Sotalol and amiodaron e had cardiodepressant effects only at doses significantly higher than the highest doses used clinically. Dofetilide did not have a negative inotropic effect at doses up to 40 ng/kg. However, these results migh t be modified in experimental models with severely compromised left ve ntricular function, as was shown for class I antiarrhythmic drugs and for d,l- and d-sotalol. The sensitivity to a drug's negative inotropic action is markedly increased in functionally impaired myocardium. Fur thermore, in a model of postischemic myocardial dysfunction, the depre ssant effect of d-sotalol could largely be avoided by previous autonom ic blockade, indicating the importance of the residual beta-blocking p otency of d-sotalol in the doses used in our experiments. Thus, in cli nically relevant doses amiodarone, d-sotalol, and dofetilide were foun d to be devoid of negative inotropic actions in the setting of normal left ventricular myocardium, In failing hearts, such effects become mo re readily evident than they do in normal hearts after high doses of a miodarone and d-sotalol. From beta-blocking experiments in hearts with left ventricular dysfunction, it could be inferred that residual beta -blocking and other negative inotropic mechanisms may produce a net ne gative inotropic action, thus masking the minor positive class III eff ects postulated from in vitro experiments. These observations may have significant clinical implications, because they suggest that the intr insic myocardial effects of antiarrhythmic drugs may be modified by au tonomic effects, the status of ventricular function, and changes in pr eload and afterload. (C) 1997 by Excerpta Medica, Inc.