title: Inhibition of ATP-sensitive K+ channels and L-type Ca2+ channels by amiodarone elicits contradictory effect on insulin secretion in MIN6 cells.
abstract: Some class I antiarrhythmic drugs induce a sporadic hypoglycemia by producing insulin secretion via inhibition of ATP-sensitive K(+) (K(ATP)) channels of pancreatic β-cells. It remains undetermined whether amiodarone produces insulin secretion by inhibiting K(ATP) channels. In this study, effects of amiodarone on K(ATP) channels, L-type Ca(2+) channel, membrane potential, and insulin secretion were examined and compared with those of quinidine in a β-cell line (MIN6). Amiodarone as well as quinidine inhibited the openings of the K(ATP) channel in a concentration-dependent manner without affecting its unitary amplitude in inside-out membrane patches of single MIN6 cells, and the IC(50) values were 0.24 and 4.9 µM, respectively. The L-type Ca(2+) current was also inhibited by amiodarone as well as quinidine in a concentration-dependent manner. Although glibenclamide (0.1 µM) or quinidine (10 µM) significantly potentiated the insulin secretion from MIN6 cells, amiodarone (1-30 µM) failed to increase insulin secretion. Amiodarone (30 µM) and nifedipine (10 µM) significantly inhibited the increase in insulin secretion produced by 0.1 µM glibenclamide. Amiodarone (30 µM) produced a gradual decrease of the membrane potential, but did not produce repetitive electrical activity in MIN6 cells. Glibenclamide (1 µM) produced a slow depolarization, followed by spiking activity which was inhibited by 30 µM amiodarone. Thus, amiodarone is unlikely to produce hypoglycemia in spite of potent inhibitory action on K(ATP) channels in insulin-secreting cells, possibly due to its Ca(2+) channel-blocking action.
authors.affiliation: Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
authors.forename: Taichi
authors.initials: T
authors.lastname: Takizawa
authors.forename: Akio
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
mesh_terms: D000638:Amiodarone / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry*; D002460:Cell Line; D005905:Glyburide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009543:Nifedipine / Q000009:adverse effects / Q000494:pharmacology; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D011802:Quinidine / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D026902:Potassium Channel Blockers; D009543:Nifedipine; D011802:Quinidine; D000638:Amiodarone; D005905:Glyburide