Inhibition of L-type Ca2+ channel current in rat ventricular myocytes by terfenadine

To elucidate possible mechanisms underlying the cardiotoxicity of terfenadine, the effect of this antihistamine on L-type Ca2+ channel current (I-Ca,I-L) was studied in adult rat ventricular myocytes using the whole-cell patch-clamp technique. Myocytes were held at -70 mV and internally dialyzed and externally perfused with Na+- and K+-free solutions; exposure to terfenadine (10(-9) to 5x10(-6) mol/L) resulted in a concentration-dependent inhibition of peak I-Ca,I-L with a half-maximum inhibition concentration (IC50) Of 142 nmol/L. The terfenadine-induced inhibition of I-Ca,I-L was not mediated via effects on histamine H-1 receptors, because 1 mu mol/L triprolidine, a more selective and potent H-1 antagonist, had no effect on I-Ca,I-L. In this study, we found that terfenadine (1) increased both the fast and slow time constants of I-Ca,I-L, inactivation, (2) shifted the steady state inactivation of I-Ca,I-L to more negative potentials, and (3) elicited a tonic block and a use-dependent block of I-Ca,I-L. The terfenadine-induced tonic and use-dependent block and the steady state inhibition of I-Ca,I-L were voltage dependent. Both tonic and use-dependent blocks of I-Ca,I-L by terfenadine at -40 mV were greater than that at -70 mV, and blocks were partially released by applying a long hyperpolarizing prepulse to -90 mV. These results suggest that terfenadine binds to L-type Ca2+ channels in inactivated and rested states and inhibits I-Ca,I-L predominantly by interacting with the inactivated state with an apparent dissociation constant of GO nmol/L. Open-state block could be observed only at high concentrations of terfenadine. The high-affinity interaction of terfenadine with the inactivated state of L-type Ca2+ channels may play an important role in its cardiotoxicity under pathophysiological conditions, such as ischemia.