Terfenadine block of sodium current in canine atrial myocytes

Terfenadine, a histamine-1 receptor antagonist, is known to have direct effects on electrical activities in the heart. Studies have demonstrated an ability of terfenadine to suppress upstroke velocity of action potential, an indication of sodium channel blockade. To clarify whether terfenadine indeed blocks sodium current (I-Na) we performed experiments to evaluate in detail the effects of terfenadine on I-Na by applying whole-cell patch-clamp techniques to canine atrial myocytes. Terfenadine produced concentration-dependent inhibition of I-Na, with a median inhibitory concentration (IC50) of 0.93 +/- 0.12 mu M. Significant effects were observed at a concentration of as low as 100 nM (similar to 15% reduction of I-Na). The effects of terfenadine on I-Na were voltage dependent, as indicated with greater inhibition at less-negative holding potentials and at more-positive test potentials. Terfenadine block ade of I-Na was characterized by an important tonic block that accounted for similar to 50% of the total block. Use-dependent block also was observed and found to contribute to 26% of the total block, and this use dependence was accentuated with longer pulse duration. Our findings suggest that terfenadine is a potent sodium channel blocker. Terfenadine blocks I-Na in both rested state and inactivated state of the channels, but preferentially interacts with the former. The I-Na-blocking property of terfenadine may contribute to its cardiac side effects in patients.