ATP-sensitive K(+) channels regulate the release of GABA in the ventromedial hypothalamus during hypoglycemia.
OBJECTIVE-To determine whether alterations in counterregulatory 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.
Chan
Owen
O
Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, 300 Cedar St., TAC S141, New Haven, CT, USA.
Lawson
Marcus
M
Zhu
Wanling
W
Beverly
Joseph Lee
JL
Sherwin
Robert S
RS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004837:Epinephrine / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D015309:Glucose Clamp Technique; D007003:Hypoglycemia / Q000503:physiopathology*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014697:Ventromedial Hypothalamic Nucleus / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001786:Blood Glucose; D007328:Insulin; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D005680:gamma-Aminobutyric Acid; D005934:Glucagon; D003981:Diazoxide; D004837:Epinephrine