title: GABA(A) receptor antagonism increases NMDA receptor inhibition by isoflurane at a minimum alveolar concentration.
abstract: OBJECTIVE
  At the minimum alveolar concentration (MAC), isoflurane potentiates GABA(A) receptor currents and inhibits NMDA receptor currents, and these actions may be important for producing anesthesia. However, isoflurane modulates GABA(A) receptors more potently than NMDA receptors. The objective of this study was to test whether isoflurane would function as a more potent NMDA receptor antagonist if its efficacy at GABA(A) receptors was decreased.
  
  
  METHODS
  Prospective experimental study.
  
  
  METHODS
  Fourteen 10-week-old male Sprague-Dawley rats weighing 269 ± 12 g.
  
  
  METHODS
  Indwelling lumbar subarachnoid catheters were surgically placed in isoflurane-anesthetized rats. Two days later, the rats were anesthetized with isoflurane, and artificial CSF containing either 0 or 1 mg kg(-1) picrotoxin, a GABA(A) receptor antagonist, was infused intrathecally at 1 μL minute(-1). The baseline isoflurane MAC was then determined using a standard tail clamp technique. MK801 (dizocilpine), an NMDA receptor antagonist, was then administered intravenously at 0.5 mg kg(-1). Isoflurane MAC was re-measured.
  
  
  RESULTS
  Picrotoxin increased isoflurane MAC by 16% compared to controls. MK801 significantly decreased isoflurane MAC by 0.72% of an atmosphere in controls versus 0.47% of an atmosphere in rats receiving intrathecal picrotoxin.
  
  
  CONCLUSIONS
  A smaller MK801 MAC-sparing effect in the picrotoxin group is consistent with greater NMDA antagonism by isoflurane in these animals, since it suggests that fewer NMDA receptors are available upon which MK801 could act to decrease isoflurane MAC. Decreasing isoflurane GABA(A) potentiation increases isoflurane NMDA antagonism at MAC. Hence, the magnitude of an anesthetic effect on a given channel or receptor at MAC may depend upon effects at other receptors.
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. rjbrosnan@ucdavis.edu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Brosnan
mesh_terms: D018685:Anesthetics, Inhalation / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000378:metabolism*; D004334:Drug Administration Schedule; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage / Q000378:metabolism*; D007263:Infusions, Parenteral; D007530:Isoflurane / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D009068:Movement / Q000187:drug effects; D010852:Picrotoxin / Q000008:administration & dosage / Q000378:metabolism*; D011446:Prospective Studies; D011650:Pulmonary Alveoli / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D018685:Anesthetics, Inhalation; D016291:Dizocilpine Maleate; D058787:GABA-A Receptor Antagonists; D007530:Isoflurane; D010852:Picrotoxin; D016194:Receptors, N-Methyl-D-Aspartate