The Characterization and Development of Electrophysiological Pharmacology Assays Testing for Potential QT Prolongation
A number of drugs with cardiac and non-cardiac targets have been implicated in cases of "torsades de pointes" (T dP), a potentially fatal arrhythmia. One of the factors in the development of this anomaly is a disruption of the heart's action potential, referred to as QT prolongation. Assays have been developed to anticipate whether a novel compound will pose a risk for T dP, but all contain drawbacks. These shortcomings lead a drive for new, improved assays. This study examined the temperature-dependent properties of an existing assay, the hERG assay, which tests a compound's inhibition on a particular type of potassium channel that is prone to drug block. A three-fold increase in the inhibition level between room and physiological temperature was found, indicating a more efficacious inhibition at higher temperatures. Other possible avenues for ion channel safety assays were also examined, including the use of primary isolated myocytes to measure effects of multi-channel block and a smooth muscle cell line (A 10) to examine a compound's potential for calcium channel block. The A I0 cells' measurable calcium currents and response to known calcium channel blockers do indicate potential for the development of a calcium channel assay. These results indicate that a vast area of expansion exists within the field of ion channel inhibition testing that could serve to improve the pharmacological analysis of novel compounds
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