title: Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons.
abstract: 1. The effects of the volatile anesthetics enflurane, halothane, and isoflurane on gamma-aminobutyric acid (GABA) receptor-mediated inhibitory postsynaptic currents (IPSCs) were studied in cultured rat hippocampal neurons. The experimental concentrations of anesthetics were measured directly using gas chromatography. All three anesthetics increased the overall duration of IPSCs, measured as the time to half-decay (T1/2). Clinically effective concentrations of anesthetics [between 0.5 and 1.5 times MAC (minimum alveolar concentration)] produced between 100 and 400% increases in T1/2. These effects were fully reversible, and did not involve alterations in the reversal potential for the IPSC (EIPSC). 2. The decay of the IPSC was fitted as a sum of two exponential functions, yielding a fast component (tau fast = 20 ms), and a slow component (tau slow = 77 ms), such that the fast component accounted for 79% of the IPSC amplitude and 52% of the total charge transfer. All three anesthetics produced concentration-related increases in the amplitude and charge transfer of the slow component, while simultaneously decreasing the amplitude and charge transfer of the fast component. Thus T1/2 approximated tau fast under control conditions, but approximated tau slow in the presence of the anesthetics. 3. Varying the calcium chelating agents in the recording pipettes had no effect on the quality or magnitude of alterations in IPSC kinetics produced by halothane, suggesting that variations in intracellular calcium levels are not required for the effect of halothane on the time course of the IPSC. 4. The (+)-stereoisomer of isoflurane produced greater increases in the duration of the IPSC than the (-)-isomer when applied at approximately equal concentrations, suggesting that there is a structurally selective site of interaction for isoflurane that modulates the GABAA receptor. 5. These results suggest that the previously shown abilities of volatile anesthetics to potentiate responses to exogenously applied GABA and to prolong the duration of GABA-mediated synaptic inhibition may be due to an alteration in the gating kinetics of the GABAA receptor/channel complex. Prolongation of synaptic inhibition in the CNS is consistent with the physiological effects that accompany anesthesia and may contribute to the mechanism of anesthetic action.
authors.affiliation: Department of Anesthesia and Critical Care, University of Chicago, Illinois 60637.
authors.forename: M V
authors.initials: MV
authors.lastname: Jones
authors.forename: N L
authors.initials: NL
authors.lastname: Harrison
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D004737:Enflurane / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006221:Halothane / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects*; D007700:Kinetics; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects; D013237:Stereoisomerism; D013569:Synapses / Q000187:drug effects*
chemical_list: D000777:Anesthetics; D002614:Chelating Agents; D007473:Ion Channels; D018079:Receptors, GABA; D004533:Egtazic Acid; D004737:Enflurane; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D006221:Halothane