Mechanisms of negative inotropic effects of class Ic antiarrhythmic agents: Comparative study of the effects of flecainide and pilsicainide on intracellular calcium handling in dog ventricular myocardium

We studied the subcellular mechanisms responsible for the negative inotropic effects of the two Ic drugs flecainide and pilsicainide. Aequorin luminescence (Ca-i(2+)) and isometric tension were recorded simultaneously in isolated trabeculae from the dog ventricle. In isolated myocytes from the same ventricle, the slow inward current (I-Ca) Was recorded. Both flecainide and pilsicainide decreased peak Ca-i(2+), peak tension, and peak I-Ca concentration dependently. Each effect with flecainide was more marked than that with pilsicainide; however, Ca-i(2+) and I-Ca paralleled each other in changes in tension, and the tension-Ca-i(2+)-I-Ca relationship showed the same curve for each drug. We conclude that the difference in negative inotropic effects of these class Ic drugs are primarily related to their effects on L-type Ca2+ channels and the subsequent decreases in the amount of Ca2+ released from the sarcoplasmic reticulum (SR) during each cardiac cycle. Therefore, their negative inotropic effects may not be directly correlated with the essential mechanisms responsible for their antiarrhythmic action.