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

Abstract

To elucidate possible mechanisms underlying the cardiotoxicity of terfenadine, the effect of this antihistamine on L-type Ca2+ channel current (ICa,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 5 x 10(-6) mol/L) resulted in a concentration-dependent inhibition of peak ICa,L with a half-maximum inhibition concentration (IC50) of 142 nmol/L. The terfenadine-induced inhibition of ICa,L was not mediated via effects on histamine H1 receptors, because 1 mumol/L triprolidine, a more selective and potent H1 antagonist, had no effect on ICa,L. In this study, we found that terfenadine (1) increased both the fast and slow time constants of ICa,L inactivation, (2) shifted the steady state inactivation of ICa,L to more negative potentials, and (3) elicited a tonic block and a use-dependent block of ICa,L. The terfenadine-induced tonic and use-dependent block and the steady state inhibition of ICa,L were voltage dependent. Both tonic and use-dependent blocks of ICa,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 ICa,L predominantly by interacting with the inactivated state with an apparent dissociation constant of 60 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.