Negative Chronotropic Effects of Class I Antiarrhythmic Drugs on Guinea Pig Right Atria: Correlation with L-Type Ca2+ Channel Blockade

Abstract

The negative chronotropic effects of eight Vaughan Williams Class I antiarrhythmic drugs were examined in guinea pig right atrial tissue preparations. The drugs decreased the spontaneous beating rate at concentrations overlapping with their therapeutic blood levels. Cibenzoline, aprindine, flecainide, and propafenone showed stronger effects; 10 µM of each drug decreased the beating rate to about 75% of initial values. Disopyramide, mexiletine, pilsicainide, and ranolazine showed weaker effects; 10 µM of each drug decreased the beating rate to about 90% of initial values. The potency of drugs correlated with the reported IC50 values to block the L-type Ca2+ channel current rather than the Na+ and K+ channel currents. The reported IC50 values for the blockade of the hyperpolarization-activated inward current (If) and the Na+-Ca2+ exchanger current were much higher than those for the blockade of the L-type Ca2+ channel current. These results indicate that the negative chronotropic effects of Class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca2+ channel.