Relationship of antiarrhythmic to inotropic activity and antiarrhythmic qualities of the optical isomers of verapamil

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Abstract
The relationship of antiarrhythmic to inotropic activity of the optical isomers of verapamil was studied by comparing their effects on functional refractory period and force of contraction in the isolated left atrium of the guinea pig and on maximum follow frequency and contractility in the dog heart. To evaluate the antiarrhythmic profile of the optical isomers of verapamil the relationship between threshold voltage and impulse duration in the left atrium of the guinea pig and the antagonistic action against ventricular arrhythmias in the rat were studied. (-)Verapamil is nearly 10 times more effective than (+)verapamil in prolonging the functional refractory period in the isolated left atrium of the guinea pig. In the dog heart (-)verapamil is about 8 times more active in reducing maximum follow frequency at atrial pacing, as well as spontaneous heart rate and in prolonging PQ-duration. In the guinea pig atrium (+)verapamil shows less negative inotropic activity than its enantiomorph. With (+)verapamil the concentration producing a 25% decrease in contractility is 3.7 times higher than that causing a 25% increase in refractory period. With (-)verapamil these concentrations are identical. In the dog i.v. infusion of the isomers, at a dosage inducing identical reduction of maximum follow frequency, is accompanied by a decrease in left ventricular dp/dt max with (-)verapamil, whereas with the (+)isomer a significant increase of dp/dt max is observed at a certain dose level. Because of the higher antiarrhythmic activity of (-)verapamil, the antiarrhythmic profile and the inotropic pattern of the racemic compound are mainly due to this isomer. (+)Verapamil shifts the voltage duration curve of the isolated left atrim of the guinea pig to the right and leads to a significant increase in the chronaxie value. (-)Verapamil has no comparable effects on the excitability of the atrial myocardium. In the intact animal (+)verapamil shows additional antiarrhythmic qualities. Like procainamide, but with higher activity, it antagonizes ventricular arrhythmias (ectopic beats, automaticity and flutter or fibrillation) which can be provoked in the rat by i.v. infusion of aconitine. (-)Verapamil and the racemic compound are ineffective against these ventricular rhythm disorders.