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Inhibition of L-type Ca2+ channel current in rat ventricular myocytes by terfenadine
S Liu1, R B Melchert, R H Kennedy
1Department of Medicine, University of Arkansas for Medical Sciences, Little Rock 72205, USA. Jliu@medlan.uams.edu
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.
Insights
Terfenadine, an antihistamine, inhibits L-type calcium channels (ICa,L) in heart cells, potentially explaining its cardiotoxicity. This drug binds strongly to inactivated calcium channels, affecting heart function.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Terfenadine, a widely used antihistamine, has been associated with cardiotoxicity.
- The precise mechanisms underlying terfenadine-induced cardiotoxicity remain incompletely understood.
- L-type calcium channels (ICa,L) play a critical role in cardiac function and are potential targets for drug-induced toxicity.
Purpose of the Study:
- To investigate the effects of terfenadine on L-type calcium channel current (ICa,L) in adult rat ventricular myocytes.
- To elucidate the specific mechanisms by which terfenadine modulates ICa,L.
- To determine the relationship between terfenadine's interaction with L-type calcium channels and its cardiotoxic potential.
Main Methods:
- Whole-cell patch-clamp technique was employed to record ICa,L in isolated adult rat ventricular myocytes.
- Terfenadine was applied at concentrations ranging from 10(-9) to 5 x 10(-6) mol/L.
- Voltage-dependence of channel block and effects on inactivation kinetics were analyzed.
Main Results:
- Terfenadine produced a concentration-dependent inhibition of peak ICa,L with an IC50 of 142 nmol/L.
- Inhibition of ICa,L was independent of histamine H1 receptor blockade.
- Terfenadine increased inactivation time constants, shifted steady-state inactivation to more negative potentials, and induced both tonic and use-dependent blocks of ICa,L.
Conclusions:
- Terfenadine inhibits ICa,L through interactions with both rested and inactivated channel states, with a predominant high-affinity binding to the inactivated state.
- The voltage-dependent nature of the block suggests a significant interaction within the cardiac action potential range.
- The high-affinity interaction of terfenadine with inactivated L-type calcium channels is a likely contributor to its cardiotoxicity, particularly under conditions like ischemia.