The PPAR alpha activator fenofibrate inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells

Abstract

We examined the effects of the PPAR alpha activator fenofibrate on voltage-dependent K+ (Kv) channels using a patch clamp technique in native rabbit coronary arterial smooth muscle cells. Kv current was inhibited by application of fenofibrate in a concentration-dependent manner, with an apparent IC50 value of 6.39 +/- 0.53 mu M and a slope value (Hill coefficient) of 1.63 +/- 0.10. Fenofibrate accelerated the decay rate of Kv channel inactivation. The rate constants of association and dissociation for fenofibrate were 0.81 +/- 0.05 mu M-1 s(-1) and 4.70 +/- 0.47 s(-1), respectively. Although fenofibrate did not affect the steady-state activation curves, fenofibrate shifted the inactivation curves toward a more negative potential. Application of train pulses (1 or 2 Hz) progressively increased the fenofibrate-induced inhibition of the Kv channel, and the recovery time constant from inactivation was increased in the presence of fenofibrate, which suggested that the inhibitory effect of fenofibrate is use-dependent. Another PPAR alpha activator, bezafibrate and PPARa inhibitor, GW 6471, did not affect the Kv current and also did not change the inhibitory effect of fenofibrate on the Kv current. From these results, we suggest that fenofibrate inhibited Kv current in a state-, time-, and use-dependent manner, completely independent of PPAR alpha activation.