The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumor cells (GH₃/B₆ cells)

Abstract

 Hyperpolarization-elicited potassium currents in GH₃/B₆ cells bathed in high-potassium external solution were recorded to assess effects of the class III antiarrhythmic agent E-4031 on the inactivating inward-rectifying potassium current (I _K,IR). E-4031 potently blocked I_K,IR with an IC₅₀ value of 10 nM. The complete block of I _K,IR achieved with concentrations ≥ 1 μM revealed the presence of a non-inactivating outward-rectifying current which contributed to the membrane currents recorded under control conditions. The time dependence of the I _K,IR block depended on the concentration of E-4031. Two other methanesulfonanilides were investigated: WAY-123,398 (10 μM) also totally blocked I _K,IR, while sotalol (100 μM) was almost ineffective. Also lanthanum (100 μM) had only a very small effect on I _K,IR. E-4031 did not affect sodium, calcium and voltage-dependent outward-rectifying potassium currents, suggesting a selective block of I _K,IR in GH₃/B₆ cells. In an external solution containing 16 mM potassium, the E-4031-sensitive current was present as a steady outward current within a broad potential range positive to the potassium equilibrium potential, E _K. In many, but not all, cells E-4031 induced an increase in the frequency of action potentials suggesting an important role of I _K,IR in controlling cell excitability. Our experiments show that E-4031 is a valuable tool in characterizing I _K,IR and its physiological function.