Title | Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Westphalen RI, Hemmings HC |
Journal | J Pharmacol Exp Ther |
Volume | 304 |
Issue | 3 |
Pagination | 1188-96 |
Date Published | 2003 Mar |
ISSN | 0022-3565 |
Keywords | 4-Aminopyridine, Anesthetics, General, Animals, gamma-Aminobutyric Acid, Glutamic Acid, Isoflurane, Male, Potassium, Rats, Rats, Sprague-Dawley, Synaptosomes |
Abstract | The role of presynaptic mechanisms in general anesthetic depression of excitatory glutamatergic neurotransmission and facilitation of GABA-mediated inhibitory neurotransmission is unclear. A dual isotope method allowed simultaneous comparisons of the effects of a representative volatile (isoflurane) and intravenous (propofol) anesthetic on the release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes). Synaptosomes were prelabeled with L-[(3)H]glutamate and [(14)C]GABA, and release was determined by superfusion with pulses of 30 mM K(+) or 1 mM 4-aminopyridine (4AP) in the absence or presence of 1.9 mM free Ca(2+). Isoflurane maximally inhibited Ca(2+)-dependent 4AP-evoked L-[(3)H]glutamate release (99 +/- 8% inhibition) to a greater extent than [(14)C]GABA release (74 +/- 6% inhibition; P = 0.023). Greater inhibition of L-[(3)H]glutamate versus [(14)C]GABA release was also observed for the Na(+) channel antagonists tetrodotoxin (99 +/- 4 versus 63 +/- 5% inhibition; P < 0.001) and riluzole (84 +/- 5 versus 52 +/- 12% inhibition; P = 0.041). Propofol did not differ in its maximum inhibition of Ca(2+)-dependent 4AP-evoked L-[(3)H]glutamate release (76 +/- 12% inhibition) compared with [(14)C]GABA (84 +/- 31% inhibition; P = 0.99) release. Neither isoflurane (1 mM) nor propofol (15 microM) affected K(+)-evoked release, consistent with a molecular target upstream of the synaptic vesicle exocytotic machinery or voltage-gated Ca(2+) channels coupled to transmitter release. These findings support selective presynaptic depression of excitatory versus inhibitory neurotransmission by clinical concentrations of isoflurane, probably as a result of Na(+) channel blockade. |
DOI | 10.1124/jpet.102.044685 |
Alternate Journal | J. Pharmacol. Exp. Ther. |
PubMed ID | 12604696 |
Grant List | GM 58055 / GM / NIGMS NIH HHS / United States |