title: Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro.
abstract: Simulated ischemic conditions (hypoxia-hypoglycaemia) in vitro enhanced glutamate efflux from rat cerebrocortical prisms. Here we characterised efflux mechanisms using pharmacological tools. The Na(+) channel blocker TTX (1 microM) did not affect ischemia-induced efflux, while sipatrigine (100 microM), a Na(+)/Ca(2+) channel blocker and omega-conotoxin MVIIC (2 microM), an N/P/Q type Ca(2+) channel blocker, inhibited efflux by fractions of 0.53 and 0.46, respectively (1.00 corresponding to total inhibition). Omission of extracellular Ca(2+) and addition of EGTA (2 mM) inhibited ischemia-induced efflux only during the first 25 min of incubation. A similar result was observed on omission of extracellular Ca(2+) together with addition of La(3+) (10 microM) and Mg(2+) (6 mM). TTX, sipatrigine and La(3+)/Mg(2+) all inhibited control efflux. Ischemia-induced efflux was sensitive to the volume activated anion channel inhibitor NPPB (100 microM) only after the first 25 min of incubation, with the maximal fraction inhibited being 0.54. The glutamate transporter inhibitor D,L-TBOA reduced ischemia-induced efflux throughout a 45-min incubation period, and enhanced efflux from control tissue. D,L-TBOA inhibited efflux at 30 min by a maximum fraction of 0.49, at 50 microM. These data indicate that the early phase of ischemia-induced glutamate efflux is in part Ca(2+) dependent, while the later phase involves volume activated anion currents and both phases involve excitatory amino acid transporters.
authors.affiliation: Pharmacology Research Group, School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Nelson
authors.forename: David G
authors.initials: DG
authors.lastname: Lambert
authors.forename: A
authors.initials: A
authors.lastname: Richard Green
authors.forename: Atticus H
authors.initials: AH
authors.lastname: Hainsworth
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002614:Chelating Agents / Q000494:pharmacology; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007811:Lanthanum / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D027322:Amino Acid Transport System X-AG; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D018118:Chloride Channels; D007473:Ion Channels; D026941:Sodium Channel Blockers; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D007811:Lanthanum; D008274:Magnesium