A new hypoglycemic agent, A-4166, inhibits ATP-sensitive potassium channels in rat pancreatic β-cells

Effects of a new hypoglycemic drug, N-[trans-4- isopropylcyclohexy- carbonyl]-D-phenylolanine (A-4166), on membrane current were investigated using the patch-clamp technique in single pancreatic β-cells isolated from rats. A-4166, at a concentration of 10 μM, depolarized membrane potential of β-cells and evoked action potentials in the presence of 2.8 mM glucose. The single ALP-sensitive K⁺ channel (K-ALP channel) current recorded in cell- attached membrane patches was reversibly inhibited by A-4166 (> 0.1 μM) without a change in the single-channel conductance of the K-ALP channel. Both A-4166 and tolbutamide inhibited the whole cell K-ALP channel current with half-maximum inhibition (IC₅₀) of 0.23 and 12.8 μM, respectively (Hill coefficient = 1). In inside-out membrane patches, the IC₅₀ with A-4166 occurred at 4.5 nM, in contrast to 0.7 μM for tolbutamide. A-4166 did not affect L- and T-type Ca²⁺ channels or the time-dependent outward current. We conclude that A-4166 specifically blocks the K-ALP channel and that the blockade is more potent than that of tolbutamide. The action of A-4166 underlies the mechanism by which the drug stimulates insulin secretion from β-cells.