Possible Involvement of Altered Na+-Ca2+ Exchange in Negative Inotropic Effects of Class I Antiarrhythmic Drugs on Rabbit and Rat Ventricles

We investigated the way in which Na+ channel blocking class I antiarrhythmic drugs, lidocaine (30 mu M), flecainide (30 mu M), and RS-2135 (100 mu M) affected contractions elicited by several protocols in rat and rabbit ventricular strips. Rabbit ventricles showed a positive force-frequency relation, and antiarrhythmic drugs inhibited the contraction, flattening the force-frequency curve. In contrast, rat ventricles showed a negative force-frequency relation, and the drugs shifted the force-frequency curve downward. Rapid-cooling contracture (RCC) also showed a positive or negative dependence on the frequency of preceding stimulation in rabbit or rat ventricles, respectively. All drugs inhibited the RCC, suggesting that they reduced the Ca2+ content in the sarcoplasmic reticulum. Ryanodine (1 mu M) abolished the RCC in both muscles and the contraction in rat muscles, but partially decreased contractions at high frequencies in rabbit ventricles. Antiarrhythmic drugs caused a further inhibition of contractions in the presence of ryanodine in rabbit ventricles. These results indicate that inhibition of Na+ channels by antiarrhythmic drugs alters Na+ -Ca2+ exchange, resulting in a decrease in the Ca2+ content in the sarcoplasmic reticulum (SR) and the Ca2+ entry through the exchanger.