High ability of zileuton ((±)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea) to stimulate IK(Ca) but suppress IK(DR) and IK(M) independently of 5-lipoxygenase inhibition

Abstract

Zileuton (Zyflo®) is regarded to be an inhibitor of 5-lipoxygenase. Although its effect on Ca²⁺-activated K⁺ currents has been reported, its overall ionic effects on neurons are uncertain. In whole-cell current recordings, zileuton increased the amplitude of Ca²⁺-activated K⁺ currents with an EC₅₀ of 3.2 μM in pituitary GH₃ lactotrophs. Furthermore, zileuton decreased the amplitudes of both delayed-rectifier K⁺ current (I_K(DR)) and M-type K⁺ current (I_K(M)). Conversely, no modification of hyperpolarization-activated cation current (I_h) was demonstrated in its presence of zileuton, although the subsequent addition of cilobradine effectively suppressed the current. In inside-out current recordings, the addition of zileuton to the bath increased the probability of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels; however, the subsequent addition of GAL-021 effectively reversed the stimulation of channel activity. The kinetic analyses showed an evident shortening in the slow component of mean closed time of BK_Ca channels in the presence of zileuton, with minimal change in mean open time or that in the fast component of mean closed time. The elevation of BK_Ca channels caused by zileuton was also observed in hippocampal mHippoE-14 neurons, without any modification of single-channel amplitude. In conclusion, except for its suppression of 5-lipoxygenase, our results indicate that zileuton does not exclusively act on BK_Ca channels, and its inhibitory effects on I_K(DR) and I_K(M) may combine to exert strong influence on the functional activities of electrically excitable cells in vivo.

Keywords: Ca(2+)-activated K(+) current; Delayed-rectifier K(+) current; Electrically excitable cell; Hyperpolarization-activated cation current; Large-conductance Ca(2+)-activated K(+) channel; M-type K(+) current; Zileuton.