The hypothalamic actions of K+ATP channel agonism

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Our current studies tested the hypothesis that a portion of the extra‐pancreatic hypoglycemic effect of glibenclamide may be mediated through actions in the central nervous system. This notion is based on our previous ex vivo neurotransmitter studies in which hypothalamic NE release was altered by glucose, 2‐DG, sulfonylureas, K + ‐channel openers and GABA‐B agonists, and our in vivo rat studies which showed that the central administration of K + ATP channel drugs affected blood glucose regulation. In the present work we tested whether extended exposure to glibenclamide results in accumulation of the drug in the brain. Albino rats were continuously administered 3H‐glibenclamide for 7, 14, 21 or 28 days via osmotic mini‐pumps. The results show that plasma levels of the drug reach equilibrium within 1 week while brain levels rise over a period of 4 weeks to achieve a higher level than seen in plasma, based on per‐weight normalizations. The findings indicate that glibenclamide appreciably accumulates in the brain and this may contribute to the overall actions of the drug which include refractory hypoglycemia and weight gain. Supported by NIH P20 RR016456 ‐04‐A1, Diabetes Trust Foundation and the HHMI.

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