GABAA receptor antagonism increases NMDA receptor inhibition by isoflurane at a minimum alveolar concentration
2011
Brosnan, Robert J.
Objective At the minimum alveolar concentration (MAC), isoflurane potentiates GABAA receptor currents and inhibits NMDA receptor currents, and these actions may be important for producing anesthesia. However, isoflurane modulates GABAA 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 GABAA receptors was decreased. Study design Prospective experimental study. Animals 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 GABAA 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 and clinical relevance 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 GABAA 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.
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