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BJA Advance Access published online on September 12, 2008
British Journal of Anaesthesia, doi:10.1093/bja/aen266
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Carbon dioxide negatively modulates N-methyl-D-aspartate receptors

R. J. Brosnan* and T. L. Pham

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA

* Corresponding author. E-mail: rjbrosnan{at}ucdavis.edu

Background: Carbon dioxide (CO2) dose-dependently decreases minimum alveolar concentration (MAC) of anaesthetics in rats. CO2 also dose-dependently decreases cerebrospinal fluid pH. N-methyl-D-aspartate (NMDA) channels exhibit pH sensitivity and are putative targets for inhaled anaesthetics. We hypothesized that CO2 dose-dependently decreases rat NMDA channel current via an acidifying effect at concentrations relevant to CO2 MAC.

Methods: To test this hypothesis, we studied rat NR1/NR2A glutamate receptors expressed in voltage-clamped Xenopus oocytes. To measure pH effects, we used perfusates adjusted between 7.3 and 5.3 with HCl. To measure CO2 effects, we used equimolar sodium perfusates containing either 0 or 24 mM NaHCO3 and CO2 between 0% and 87% atm. Solution compositions were measured using a blood gas analyser with values corrected using a calibrated pH meter and gas chromatograph with solutions at 37°C.

Results: We found that decreasing pH decreased NMDA current. Moreover, pH effects produced by adding CO2 to NaHCO3-containing perfusates were identical to those produced by adding HCl to normal perfusates. The pH inhibiting 50% of NMDA current was 6.52. The CO2 concentration inhibiting 50% of rat NMDA current was 63% for solutions with 24 mM NaHCO3. CO2 exhibited a linear dose-dependent NMDA response analogous to that observed for in vivo CO2 anaesthetic potency in rats.

Conclusions: CO2 and hydrogen ions act via the same mechanism to inhibit NMDA receptors. Moreover, CO2 inhibits rat NMDA receptors in a manner that is consistent with CO2 MAC-sparing effects in rats.

Keywords: anaesthesia; anaesthetic gases; carbon dioxide; hypercapnia; ion channels; N-methyl-D-aspartate; pH; receptor pharmacology


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