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

Abstract

1 The sulphonylureas, tolbutamide (0.1-10mM) and glibenclamide (0.1-100/pM) 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 cellattached recordings from glucoreceptive VMHN neurones. 5 Glibenclamide (10-500nM) 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.

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

“…The K ATP channel is considered the effector of glucosensing in GE neurons (5,54). However, the Kir6.2 subunit was expressed in only 42% of the GE and GI neurons.…”

Activation of ATP-sensitive K+(KATP) channels by H2O2underlies glutamate-dependent inhibition of striatal dopamine release

“…Significantly, however, these metabolically sensitive channels can be activated also under normal physiological conditions. For example, in the hypothalamus, K ATP channels in glucose-sensitive and -responsive cells contribute to the regulation of systemic glucose homeostasis (32)(33)(34); in the brainstem, these channels control the excitability of vagal neurons (35) and medullary respiratory cells (36). Whether K ATP channels modulate CNS-transmitter release under nonpathological conditions and what factors regulate channel opening, however, have not been established.…”

Regulation of a potassium conductance in rat midbrain dopamine neurons by intracellular adenosine triphosphate (ATP) and the sulfonylureas tolbutamide and glibenclamide

“…The block by the sulfonylureas tolbutamide (100 pM) and glibenclamide (3 pM) of the hyperpolarization/outward current resulting from dialysis with ATP-free solution is a characteristic of K-ATPs in ventromedial hypothalamic neurons (Ashford et al, 1990). The effective concentrations were 14 orders of magnitude greater than the affinity of sulfonylureas at the high-affinity binding site for "H-glibenclamide (see Ashcroft and Ashcroft, 1992, for review), suggesting that the site bound by sulfonylureas to block these K-ATPs may not be that labeled with high affinity by 'H-glibenclamide.…”