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

Abstract

1. Previous studies on verapamil and D600 have established that the Ca2+ -channel blockers also inhibit delayed-rectifier K+ currents in cardiac tissues and myocytes. However, estimated IC50 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. 2. 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 μM to 3 mM verapamil and D600 on the inwardly-rectifying K+ current (IKl) and the two delayed-rectifier K+ currents, rapidly-activating IKr and slowly-activating IKs. 3. The phenylalkylamines inhibited both inward- and outward-directed IKl. The IC50 values for outward IKl were approximately 220 μM. 4. Verapamil and D600 were approximately equipotent inhibitors of the delayed-rectifier K+ currents. They inhibited IKr with IC50 near 3 μM, and IKs with IC50 ≥ 280 μM. These results are discussed in relation to previous findings on K+ currents and to the clinical actions of the drugs.