Inhibition of the ATP‐sensitive potassium channel by class I antiarrhythmic agent, cibenzoline, in rat pancreatic β‐cells

Abstract

1 Cibenzoline, a class I antiarrhythmic agent, was investigated for its effect on the ATP-sensitive K+ channel of pancreatic P-cells by the patch clamp technique.2 In perforated patch clamp experiments, cibenzoline depolarized the membrane of single a-cells and thereafter, caused firing of action potentials in the presence of 2.8 mM glucose. 3 Cibenzoline inhibited the activity of the ATP-sensitive K+ channel in cell-attached recordings in the presence of 2.8 mM glucose and evoked repetitive fluctuations of the baseline current, apparently reflecting the action potentials of the a-cell. 4 In whole-cell clamp experiments, time-independent outward current was induced by depleting cytoplasmic ATP with 0.1 mM ATP and 0.1 mM ADP in the solution contained in the pipette. The outward current was inhibited by cibenzoline in a dose-dependent manner in the concentration range of 1 tLM to 100 iLM and half maximum inhibition occurred at 1.5 riM.5 Cibenzoline blocked substantially the ATP-sensitive K+ channel current when applied at the inner side of the membrane in isolated inside-out membrane patches.6 It is concluded that cibenzoline blocks the ATP-sensitive K+ channel of pancreatic P-cells and, thereby, stimulates insulin secretion at sub-stimulatory levels of glucose.

Block of pancreatic ATP‐sensitive K+ channels and insulinotrophic action by the antiarrhythmic agent, cibenzoline

“…The cibenzoline half-block concentrations (IC50) for # cell KATP channels were 1.5-2.5 gIM Kakei et al, 1993), which are very close to the therapeutic concentrations of the drug (-1 jIM: Massarella et al, 1986). Supposing these relative values also to be the case in humans, it would be expected that most patients receiving the drug would experience hypoglycaemia.…”

“…In earlier papers (Hone et al, 1992;Kakei et al, 1993), cibenzoline at < 3 gM has been found to inhibit KATP channel activities recorded in excised inside-out patches when applied to the cytosolic side of membrane. The half blocking cibenzoline concentrations (IC50) so far reported are, however, > 10 fold lower than the EC50 value for its insulin-secreting action (94.2 gM).…”

Pathways in Beta-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues

“…In vitro studies have shown that they increase insulin secretion by closing ␤-cell K ATP channels through a direct interaction with K ϩ IR 6.2. Among these drugs are antimalarial quinolines such as quinine and mefloquine (54,55), antibacterial fluoroquinolones such as norfloxacin and lomefloxacin (56), antiarrhythmic agents such as disopyramide and cibenzoline (57)(58)(59), and others (60).…”

Inhibition of ATP-Sensitive K+ Channels and L-Type Ca2+ Channels by Amiodarone Elicits Contradictory Effect on Insulin Secretion in MIN6 Cells

“…Several studies have indicated that the drug-induced hypoglycemia can be ascribed to insulin secretion from pancreatic β-cells resulting from ATP-sensitive K + (K ATP )-channel inhibition (3,4). Amiodarone is the most effective antiarrhythmic drug that suppresses sudden cardiac death by its antifibrillatory activity (5,6).…”