Bepridil differentially inhibits two delayed rectifier K + currents, I Kr and I Ks , in guinea‐pig ventricular myocytes

We investigated the effects of bepridil on the two components of the delayed rectifier K + current, i.e., the rapidly activating (I Kr ) and the slowly activating (I Ks ) currents using tight‐seal whole‐cell patch‐clamp techniques in guinea‐pig ventricular myocytes, under blockade of L‐type Ca 2+ current with nitrendipine (5 μ M ) or D600 (1 μ M ). Bepridil decreased I Ks under blockade of I Kr with E4031 (5 μ M ), in a concentration‐dependent manner. The concentration‐dependent inhibition of I Ks by bepridil was fitted by a curve, assuming one‐to‐one interactions between the channel and the drug molecule. The concentration of half‐maximal inhibition (IC 50 ) was found to be 6.2 μ M . The effect of bepridil on I Kr was assessed using an envelope‐of‐tails test. In the control condition, a ratio of the tail current to the time‐dependent current measured during depolarization was large (>1) at shorter pulses (<200 ms), and it decreased to a steady state value of ∼0.4 with increases in the pulse duration. Bepridil at a concentration of 2 μ M did not decrease this ratio at shorter pulses. In a short‐pulse (duration=50 ms) experiment that largely activates I Kr , the drug was found to block I Kr in a cooperative manner (Hill coefficient=3.03) and the IC 50 was 13.2 μ M . These results suggest that bepridil at a clinical therapeutic concentration (∼2 μ M ) selectively blocks I Ks but does not inhibit I Kr . This may relate to the characteristic frequency‐dependent effects of bepridil on the action potential duration (APD), e.g., the non‐reverse use‐dependent prolongation of APD.British Journal of Pharmacology (1999) 128 , 1733–1738; doi: 10.1038/sj.bjp.0702959