Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K+ channels.
1. The sulphonylureas, tolbutamide (0.1-10 mM) and glibenclamide (0.1-100 microM) 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 hypothalamic 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.
Ashford
M L
ML
Department of Pharmacology, University of Cambridge.
Boden
P R
PR
Treherne
J M
JM
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005905:Glyburide / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology*; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005905:Glyburide