Synergistic inhibition of delayed rectifier K ⁺ and voltage-gated Na ⁺ currents by artemisinin in pituitary tumor (GH ₃ ) cells

Background: Artemisinin (ART) is an anti-malarial agent reported to influence endocrine function. Methods: Effects of ART on ionic currents and action potentials (APs) in pituitary tumor (GH ₃ ) cells were evaluated by patch clamp techniques. Results: ART inhibited the amplitude of delayed-rectifier K ⁺ current (I _K(DR) ) in response to membrane depolarization and accelerated the process of current inactivation. It exerted an inhibitory effect on I _K(DR) with an IC ₅₀ value of 11.2 μM and enhanced I _K(DR) inactivation with a K _D value of 14.7 μM. The steady-state inactivation curve of I _K(DR) was shifted to hyperpolarization by 10 mV. Pretreatment of chlorotoxin (1 μM) or iloprost (100 nM) did not alter the magnitude of ART-induced inhibition of I _K(DR) in GH ₃ cells. ART also decreased the peak amplitude of voltage-gated Na ⁺ current (I _Na ) with a concentration-dependent slowing in inactivation rate. Application of KMUP-1, an inhibitor of late I _Na , was effective at reversing ART-induced prolongation in inactivation time constant of I _Na . Under current-clamp recordings, ART alone reduced the amplitude of APs and prolonged the duration of APs. Conclusion: Under ART exposure, the inhibitory actions on both I _K(DR) and I _Na could be a potential mechanisms through which this drug influences membrane excitability of endocrine or neuroendocrine cells appearing in vivo.