Electrophysiological Evidence for the Inhibition of Potassium Permeability in Pancreatic Β‐cells by Glibenclamide

Abstract

SUMMARYThe effects of glibenclamide on the electrical activity of the fl-cells of the islets of Langerhans of normal mice have been investigated in the absence and presence of glucose (11 1 mM). Glibenclamide depolarized the cell membrane and this has been interpreted in terms of an increase in the ratio of the Na+ and K+ permeabilities, PNa/PK. This ratio increased from 0 05 to 0 24 in the presence of 4 /tM glibenclamide and zero glucose. The input resistance of the fl-cells also increased. These observations indicate a decrease in K+ permeability. The effect is only slowly reversed after removal of glibenclamide. Uncouplers of oxidative phosphorylation do not reverse the depolarization induced by glibenclamide. It is suggested that glibenclamide is acting directly to inhibit the [Ca2+]i-gated K+ permeability in the fl-cell membrane.

MEMBRANE POTENTIAL MEASUREMENTS IN ISLETS OF LANGERHANS FROM ob/ob OBESE MICE SUGGEST AN ALTERATION IN [Ca2+]i‐ACTIVATED K+ PERMEABILITY

“…The effects of CCmCP on the glucose-induced electrical activity in most ob/ob fl-cells examined here are very similar to those observed in normal fl-cells (Rosario, 1983;Ferrer et al 1984). Effects ofquinine on membranepotentials andglucose-inducedelectricalactivity in ob/ob ,8-cells In normal fl-cells, quinine blocks the silent phase of glucose-induced bursts of electrical activity generating a pattern of constant spike activity (Atwater et al 1979).…”

“…In normal islets, glibenclamide effects are slowly reversible (Meissner & Atwater, 1976). More recently, glibenclamide has been proposed to be 25 times more effective than quinine in blocking the [Ca2+]1-activated K+ permeability in normal fl-cells (Ferrer et al 1984). In the ob/ob islets, glibenclamide was only effective in two out of nine islets, and then only at concentrations 100 times the effective concentration in normal fl-cells.…”

“…This may be related to factors controlling the cytosolic Ca2+ buffering in ob/ob fl-cells (Atwater et al 1979;Atwater, 1980;Atwater, Rosario & Rojas, 1983) or both. To investigate further these possibilities, a mitochondrial uncoupler, carbonylcyanide m-chlorophenylhydrazone (CCmCP), and two blockers of the K+ permeability, quinine (Atwater et al 1979) and glibenclamide (Ferrer et al 1984), were tested. The results are presented in the following sections.…”

Differential effects of the K+ channel blockers apamin and quinine on glucose‐induced electrical activity in pancreatic β‐cells from a strain of ob/ob (obese) mice

“…Indeed, exposure to apamin depolarized the ob/ob @cell membrane as is the case for quinine in islets from normal mouse [2] and, furthermore, the toxin impaired the hyperpolarizing effect of CCCP. This uncoupler of oxidative phosphorylation has been reported to hyperpolarize the P-cell membrane through activation of Px-Ca, leading to cessation of spike activity, both in islets from albino mice [14] and from ob/ob mice [9]. In addition, apamin affected the spike characteristics.…”

Adamantane derivatives: a new class of insulin secretagogues

“…The same sequence of events is also believed to underlie the effects of sulphonylureas of the first and second generation (Henquin, 1980;Henquin & Meissner, 1982;Matthews & Shotton, 1984a;Ferrer et al, 1984) and of benzoic acid derivatives of the sulphonylureas of second generation (Garrino et al, 1985;. In contrast to all these agents, 1-adamantanamine may also affect intracellular Ca2" stores without this effect being sufficient to trigger release.…”