Tolbutamide excites rat glucoreceptive ventromedial hypothallamic neurones by indirect inhibition of ATP‐K+ channels

Abstract

1 The sulphonylureas, tolbutamide (0.1–10 mm) and glibenclamide (0.1–100 μm) were shown not to inhibit ATP-K⁺ channel currents when applied to inside-out membrane patches excised from rat cultured cerebral cortex or freshly-dispersed ventromedial hypothalmic nucleus (VMHN) neurones. 2 Saturable binding sites for [³H]-glibenclamide, with similar affinity constants are present in rat cerebral cortex and hypothalamic membranes. The density of binding sites was lower in the hypothalamus than cortex. 3 Intracellular recordings from glucoreceptive VMHN neurones in hypothalamic slices were obtained. In the absence of glucose, tolbutamide (0.1 mm) depolarized these cells, increased membrane resistance and elicited action potentials. 4 Tolbutamide (0.1 mm) inhibited ATP-K⁺ channel currents and induced action current activity in cell-attached recordings from glucoreceptive VMHN neurones. 5 Glibenclamide (10–500 nm) had no effect per se on glucoreceptive VMHN neurones but did antagonize the actions of tolbutamide. 6 It is concluded that the hypothalamic (and perhaps cortical) sulphonylurea receptors are not directly coupled to ATP-K⁺ channels.