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 ino tropic effects of the two Ic drugs flecainide and pilsicainide. Aequor in luminescence (Ca-i(2+)) and isometric tension were recorded simulta neously in isolated trabeculae from the dog ventricle. In isolated myo cytes from the same ventricle, the slow inward current (I-Ca) Was reco rded. Both flecainide and pilsicainide decreased peak Ca-i(2+), peak t ension, and peak I-Ca concentration dependently. Each effect with flec ainide 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 con clude that the difference in negative inotropic effects of these class Ic drugs are primarily related to their effects on L-type Ca2+ channe ls and the subsequent decreases in the amount of Ca2+ released from th e sarcoplasmic reticulum (SR) during each cardiac cycle. Therefore, th eir negative inotropic effects may not be directly correlated with the essential mechanisms responsible for their antiarrhythmic action.