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Native and cloned ion channels from human heart: laboratory models for evaluating the cardiac safety of new drugs

I. Caveroa,1 and W. Crumb2

1 34, rue Victor Hugo, 94380 Bonneuil sur Marne, France
2 Zenas Technologies L.L.C., 5896 Fleur de Lis Drive, New Orleans, LA 70124, U. S. A.

a Correspondence: Icilio Cavero, 34, rue Victor Hugo, 94380 Bonneuil sur Marne, France.

Abstract

A number of drugs currently in clinical use cause unwanted prolongation of the QT interval. This condition occasionally evolves to fatal, polymorphic ventricular dysrhythmias. A posteriori, many of these drugs, at clinically relevant concentrations, have been shown to block the ionic current carried by the HERG channel, a major player in the repolarization process by which the heart recovers its resting state. This article describes an experimental strategy designed to reveal possible mechanisms by which drugs may delay ventricular repolarization. This strategy is designed to determine the ability of these compounds to block K+ conductance in HERG channels. In view of the difficulties involved in studying such channels in their natural location, they are expressed in mammalian cells and are studied under whole-cell patch clamp configuration. For the novel drugs that are candidates to further development, cardiac safety examination should be extended to other major ion channels of human myocardium. The activity of such channels can be recorded by patch clamp techniques in myocytes disaggregated from atrial tissue specimens excised during elective cardiac surgery. The experimental conditions adopted for these experiments should replicate, as closely as possible, the physiological environment embracing the native channels. The effects of various compounds on the HERG channel are reported and a method for calculating cardiac safety indices is described and applied to terfenadine and cetirizine. These indices are useful tools for deciding whether a candidate drug deserves to enter the development pathway. In conclusion, patch clamp studies in cloned and native human heart ion channels can provide fundamental information concerning the cardiac safety profile of novel drugs intended for use in humans.

Key Words: Human cardiac ion channels • cardiac safety screening • drugs prolonging QT interval

References

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