Bepridil block of recombinant human cardiac IKs current shows a time-dependent unblock.

Yoshihiro Yumoto, Minoru Horie, Tomoyuki Kubota, Tomonori Ninomiya, Atsushi Kobori, Kotoe Takenaka, Makoto Takano, Shinichi Niwano, Tohru Izumi

Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara City, Japan.

Journal of cardiovascular pharmacology 2004 Feb

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Whole-cell patch-clamp techniques were employed to examine the effects of bepridil, a Ca2+ channel blocker with Vaughan Williams class III action, on a slow component of cardiac delayed rectifier K+ current (IKs), which was reconstituted in HEK293 cells by transfecting KCNQ1 and KCNE1. Micromolar bepridil inhibited tail currents carried by KCNQ1/KCNE1 channels in a concentration-dependent manner (IC50 = 5.3 +/- 0.7 microM at -40 mV from 1000 milliseconds test pulse). When the effect of the drug was examined with a short test pulse protocol (250 milliseconds), IC50 became two-fold smaller than that measured with 1000 milliseconds test pulse (2.5 +/- 0.8 microM). The envelope-of-tails protocol was used to assess how the duration of depolarizing pulse affects the drug action on the outward KCNQ1/KCNE1 channel current. The drug significantly inhibited tail currents more potently during shorter pulses (<600 milliseconds). Bepridil's block was therefore time dependent, and its binding affinity to the channel was greater in the closed state channel, as evidenced by unblocking during prolonged depolarization. These properties of channel blockade appear to underscore the mechanism of bepridil's effect on IKs current.

Citation

Yoshihiro Yumoto, Minoru Horie, Tomoyuki Kubota, Tomonori Ninomiya, Atsushi Kobori, Kotoe Takenaka, Makoto Takano, Shinichi Niwano, Tohru Izumi. Bepridil block of recombinant human cardiac IKs current shows a time-dependent unblock. Journal of cardiovascular pharmacology. 2004 Feb;43(2):178-82