The lack of bicuculline and picrotoxin influence on midazolam depressant action on brain oxygen consumption.
In the previous study of the rat frontal cortex slices oxygen consumption (QO2), polarographically determined using the biological oxygen monitor, a moderate respiratory depressant action of midazolam ex vivo (1.0 mg/kg) has been observed. Antagonist of the benzodiazepine binding site, flumazenil, blocked the effect of the agonist. However, midazolam-gamma-aminobutyric acid (GABA) interactions pointed to the possibility that a part of midazolam action is independent of the classical GABA potentiation. To test this presumption, GABAA receptor antagonists bicuculline and picrotoxin were administered. Both blockers antagonized the QO2 reducing effect of the combination of per se effective doses of midazolam (1.0 mg/kg) and GABA (5 x 10(-4) mol/l), as well as of GABA (5 x 10(-4) mol/l) itself. However, neither effects of midazolam (1.0 mg/kg) on its own, nor those of midazolam in presence of the physiological, per se ineffective, concentration of GABA (10(-6) mol/l), were susceptible to antagonism. These results show that ex vivo influence of midazolam on cerebral metabolic activity should be partly ascribed to some of its cellular mechanisms probably associated to the GABA modulation, but distinct from the standard GABA-potentiating effects of benzodiazepines.
Obradović
Dragan I
DI
Department of Pharmacology, Medical Faculty, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia and Montenegro.
Savić
Miroslav M
MM
Obradović
Miljana M
MM
Ugresić
Nenad D
ND
Bokonjić
Dubravko R
DR
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology*; D004347:Drug Interactions; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D018757:GABA Modulators / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects*; D010852:Picrotoxin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D001640:Bicuculline; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D008874:Midazolam; D010852:Picrotoxin