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(Circulation Research. 1997;81:202-210.)
© 1997 American Heart Association, Inc.

Articles

Inhibition of L-Type Ca²⁺ Channel Current in Rat Ventricular Myocytes by Terfenadine

Shi Liu, Russell B. Melchert, , Richard H. Kennedy

From the Department of Medicine, Division of Cardiology (S.L.), the Department of Biopharmaceutical Sciences (R.B.M.), and the Department of Pharmacology and Toxicology (S.L., R.H.K.), University of Arkansas for Medical Sciences, Little Rock.

Abstract To elucidate possible mechanisms underlying the cardiotoxicity of terfenadine, the effect of this antihistamine on L-type Ca²⁺ channel current (I_Ca,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,L, with a half-maximum inhibition concentration (IC₅₀) of 142 nmol/L. The terfenadine-induced inhibition of I_Ca,L was not mediated via effects on histamine H₁ receptors, because 1 µmol/L triprolidine, a more selective and potent H₁ antagonist, had no effect on I_Ca,L. In this study, we found that terfenadine (1) increased both the fast and slow time constants of I_Ca,L inactivation, (2) shifted the steady state inactivation of I_Ca,L to more negative potentials, and (3) elicited a tonic block and a use-dependent block of I_Ca,L. The terfenadine-induced tonic and use-dependent block and the steady state inhibition of I_Ca,L were voltage dependent. Both tonic and use-dependent blocks of I_Ca,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,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.

Key Words: terfenadine • Ca²⁺ channel • cardiac myocyte • rat • use-dependent block

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