ATP-sensitive K+ channels regulate the release of GABA in the ventromedial hypothalamus during hypoglycemia

OBJECTIVE-To determine whether alterations in counter-regulatory responses to hypoglycemia through the modulation of ATP-sensitive K+ channels (K-ATP channels) in the ventromedial. hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing K-ATP channels in the VMH alter local GABA levels and whether the effects of modulating K-ATP channel activity within the VMH can be reversed by local modulation of GABA receptors. RESEARCH DESIGN AND METHODS-Rats were cannulated and bilateral guide cannulas inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the K-ATP channel opener diazoxide, 3) the K-ATP channel closer glybenclamide, 4) diazoxide plus the GABA(A) receptor agonist muscimol, or 5) glybenclamide plus the GABA(A) receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis. RESULTS-As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of K-ATP modulators were reversed by GABA(A) receptor agonism and antagonism, respectively. Microdialysis revealed that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%. CONCLUSIONS-Our data suggests that K-ATP channels within the VMH may modulate the magnitude of counterregulatory responses by altering release of GABA within that region.