The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumor cells (GH3/B6 cells).
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 (IK,IR). E-4031 potently blocked IK,IR with an IC50 value of 10 nM. The complete block of IK,IR achieved with concentrations >/= 1 microM 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 IK,IR block depended on the concentration of E-4031. Two other methanesulfonanilides were investigated: WAY-123,398 (10 microM) also totally blocked IK,IR, while sotalol (100 microM) was almost ineffective. Also lanthanum (100 microM) had only a very small effect on IK,IR. E-4031 did not affect sodium, calcium and voltage-dependent outward-rectifying potassium currents, suggesting a selective block of IK,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, EK. In many, but not all, cells E-4031 induced an increase in the frequency of action potentials suggesting an important role of IK,IR in controlling cell excitability. Our experiments show that E-4031 is a valuable tool in characterizing IK,IR and its physiological function.
Weinsberg
F
F
Physiologisches Institut, Universitäts-Krankenhaus Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
Bauer
C K
CK
Schwarz
J R
JR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D010880:Piperidines / Q000494:pharmacology*; D010911:Pituitary Neoplasms / Q000188:drug therapy; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031