EO-199, a specific antagonist of antiarrhythmic drugs: assessment by binding experiments and in vivo studies.

EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class IA). EO-199 did not block significantly the activity of a class IB antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of [3H]EO-122 to rat heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (IA) but not lidocaine (IB), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

Effect of procainamide on myocardial contractile function and digoxin inotropy.

The effect of procainamide and digoxin, singly and together, on peak active force and rate of force development of isolated right ventricular papillary muscles from adult cats was examined. Procainamide (1.5 X 10(-5) M) increased force and rate of force development in each muscle with further increments in performance up to 2.4 X 10(-4) M in most muscles. The maximal increases in force (+/- SEM) averaged 75 +/- 13% above control values. Essentially no response to procainamide was observed when basal levels of contractile state were increased by increasing stimulus frequency or calcium concentrations of the bathing solution. Propranolol (10(-6) M) markedly reduced and verapamil (10(-7) M) abolished the inotropic effect of procainamide. Exposing muscles to procainamide (1.5 or 3 X 10(-5) M) before or after the administration of digoxin (2 or 4 X 10(-7) M) did not alter the inotropic action of either drug. Thus, procainamide in concentrations that are in the therapeutic range in human patients has potent positive inotropic effects that may be masked at high levels of contractile state. This action of procainamide appears to be due to an effect on calcium channels, which in part may be due to beta-adrenergic receptor stimulation. These concentrations of procainamide do not alter the inotropic response to digoxin.

Influence of glucagon on the cardiovascular effects of procainamide.

Effects of glucagon on procainamide-induced cardiac toxicity were studied in anesthetized dogs. Procainamide in doses of 50 and 100 mg/kg produced dose-dependent decreases in the blood pressure, cardiac output, left ventricular work index, and left ventricular systolic pressure; and increases in the left ventricular end diastolic and right atrial pressure, and total systemic vascular resistance. Glucagon antagonized most of the effects of procainamide on the cardiovascular system. Glucagon may be effective in antagonizing procainamide-induced cardiac toxicity.