Selective phenylalkylamine block of IKr over other K⁺ currents in guinea‐pig ventricular myocytes

Previous studies on verapamil and D600 have established that the Ca 2+ ‐channel blockers also inhibit delayed‐rectifier K + currents in cardiac tissues and myocytes. However, estimated IC 50 values range over two to three orders of concentration, and it is unclear whether this reflects a high selectivity by one or both of the phenylalkylamines for particular K + channels. The purpose of the present study was to determine the concentration‐dependent actions of verapamil and D600 on three defined cardiac K + currents. Guinea‐pig ventricular myocytes in the conventional whole‐cell configuration were bathed with normal Tyrode's or K + ‐free solution, and pulsed from −80 mV for measurement of the effects of 0.01 μ M to 3 m M verapamil and D600 on the inwardly‐rectifying K + current ( I Kl ) and the two delayed‐rectifier K + currents, rapidly‐activating I Kr and slowly‐activating I Ks . The phenylalkylamines inhibited both inward‐ and outward‐directed I Kl . The IC 50 values for outward I Kl were approximately 220 μ M . Verapamil and D600 were approximately equipotent inhibitors of the delayed‐rectifier K + currents. They inhibited I Kr with IC 50 near 3 μ M , and I Ks with IC 50 280 μ M . These results are discussed in relation to previous findings on K + currents and to the clinical actions of the drugs. British Journal of Pharmacology (2000) 131 , 1809–1816; doi: 10.1038/sj.bjp.0703758