Increased GABA release in the human brain cortex as a potential pathogenetic basis of hyperosmolar diabetic coma.
Human cerebral cortical slices preincubated with [3H]GABA, [3H]noradrenaline, or 5-[3H]hydroxytryptamine and superfused with Krebs solution or Mg(2+)-free Krebs solution were used to investigate the influence of increased D-glucose concentrations on the release of these [3H]-neurotransmitters evoked by high K+ content or NMDA receptor activation, respectively. An increase in level of D-glucose (normal content, 11.1 mM) by 32, 60, and/or 100 mM (a range characteristic for hyperosmolar diabetic coma) increased the [3H]GABA release and inhibited the [3H]noradrenaline release evoked by both methods of stimulation. The K(+)-induced 5-[3H]hydroxytryptamine release was also inhibited by high D-glucose content. Blockade of GABAB receptors by p-(3-aminopropyl)-p-diethoxymethylphosphinic acid (CGP 35348) attenuated the inhibitory effect of high D-glucose content on the K(+)-evoked release of [3H]noradrenaline and 5-[3H]hydroxytryptamine, suggesting that the effect on monoamine release is, at least to a major part, the result of the increased GABA release and, as a consequence, of an increased GABA concentration at inhibitory GABAB receptors. The membrane-impermeable sorbitol mimicked the increasing effect of D-glucose on [3H]GABA release and its inhibitory effect on 5-[3H]hydroxytryptamine release. However, dimethyl sulfoxide, which is known to permeate rapidly through biological membranes, had no effect at concentrations equiosmolar to D-glucose. It is concluded that a reduction in brain cell volume caused by increased extracellular, compared with cytoplasmic, osmolarity is crucial for the changes in neuronal function observed at high D-glucose and sorbitol content.(ABSTRACT TRUNCATED AT 250 WORDS)
Fink
K
K
Institute of Pharmacology and Toxicology, University of Bonn, F.R.G.
Zentner
J
J
Göthert
M
M
D000328:Adult; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003926:Diabetic Coma / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D018756:GABA Antagonists; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D009994:Osmolar Concentration; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D014316:Tritium; D012701:Serotonin; D013012:Sorbitol; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; C066430:CGP 35348; D005947:Glucose; D011188:Potassium; D009638:Norepinephrine