THE CLASS-III ANTIARRHYTHMIC AGENT E-4031 SELECTIVELY BLOCKS THE INACTIVATING INWARD-RECTIFYING POTASSIUM CURRENT IN RAT ANTERIOR-PITUITARYTUMOR-CELLS (GH(3) B-6 CELLS)/

Hyperpolarization-elicited potassium currents in GH(3)/B-6 cells bathe d in high-potassium external solution were recorded to assess effects of the class III antiarrhythmic agent E-4031 on the inactivating inwar d-rectifying potassium current (I-K,I-IR). E-4031 potently blocked I-K ,I-IR with an IC50 value of 10 nM. The complete block of I-K,I-IR achi eved with concentrations greater than or equal to 1 mu M revealed the presence of a non-inactivating outward-rectifying current which contri buted to the membrane currents recorded under control conditions. The time dependence of the I-K,I-IR block depended on the concentration of E-4031. Two other methanesulfonanilides were investigated: WAY-123,39 8 (10 mu M) also totally blocked I-K,I-IR, while sotalol (100 mu M) wa s almost ineffective. Also lanthanum (100 mu M) had only a very small effect on I-K,I-IR. E-4031 did not affect sodium, calcium and voltage- dependent outward-rectifying potassium currents, suggesting a selectiv e block of I-K,I-IR in GH(3)/B-6 cells. In an external solution contai ning 16 mM potassium, the E-4031-sensitive current was present as a st eady outward current within a broad potential range positive to the po tassium 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,I-IR in controlling cell excitability. Our ex periments show that E-4031 is a valuable tool in characterizing I-K,I- IR and its physiological function.