Na+/Ca2+ Exchanger-Mediated Negative Inotropy of Na+ Channel Blockers Pilsicainide, Cibenzoline, and Propafenone in Guinea Pig Ventricular Myocardial Tissue Preparations

Involvement of the Na+/Ca2+ exchanger (NCX) in the negative inotropic effects of class I antiarrhythmic drugs, pilsicainide, cibenzoline, and propafenone, was examined in isolated guinea pig ventricular myocardium. The class I antiarrhythmic drugs, as well as tetrodotoxin, decreased contractile force in a concentration-dependent manner; the magnitude of the effect was propafenone > cibenzoline > pilsicainide. Under conditions of NCX inhibition with the NCX inhibitor SEA0400 or with a low-Na+ extracellular solution, the negative inotropic effects of the class I antiarrhythmic drugs were attenuated. While the effect of pilsicainide was almost abolished, the inhibition was only partial for cibenzoline and propafenone. These results suggest that NCX facilitation secondary to Na+ channel blockade constitutes a common mechanism underlying the negative inotropic effects of class I antiarrhythmic drugs. Drugs with stronger negative inotropic effects have additional mechanisms, and the overall magnitude of negative inotropy is determined by the sum of these actions.