Jc. Wang et al., Bepridil differentially inhibits two delayed rectifier K+ currents, I-Kr and I-Ks, in guinea-pig ventricular myocytes, BR J PHARM, 128(8), 1999, pp. 1733-1738
1 We investigated the effects of bepridil on the two components of the dela
yed rectifier K+ current, i.e., the rapidly activating (I-Kr) and the slowl
y activating (I-Ks) currents using tight-seal whole-cell patch-clamp techni
ques in guinea-pig ventricular myocytes, under blockade of L-type Ca2+ curr
ent with nitrendipine (5 mu M) or D600 (1 mu M).
2 Bepridil decreased I-Ks under blockade of I-Kr with E4031 (5 mu 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 bet
ween the channel and the drug molecule. The concentration of half-maximal i
nhibition (IC50) was found to be 6.2 mu M.
3 The effect of bepridil on I-Kr was assessed using an envelope-of-tails te
st. In the control condition, a ratio of the tail current to the time-depen
dent current measured during depolarization was large (>1) at shorter pulse
s (<200 ms), and it decreased to a steady state value of similar to 0.4 wit
h increases in the pulse duration. Bepridil at a concentration of 2 mu M di
d not decrease this ratio at shorter pulses.
4 In a short-pulse (duration = 50 ms) experiment that largely activates I-K
r, the drug was found to block I-Kr in a cooperative manner (Hill coefficie
nt=3.03) and the IC50 was 13.2 mu M.
5 These results suggest that bepridil at a clinical therapeutic concentrati
on (similar to 2 mu M) selectively blocks I-Ks but does not inhibit I-Kr. T
his may relate to the characteristic frequency-dependent effects of bepridi
l on the action potential duration (APD), e.g., the non-reverse use-depende
nt prolongation of APD.