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

Robert J Brosnan, T. L. Pham

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 NaHCO 3. 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.

Original languageEnglish (US)
Pages (from-to)673-679
Number of pages7
JournalBritish Journal of Anaesthesia
Volume101
Issue number5
DOIs
StatePublished - Nov 2008

Fingerprint

Carbon Dioxide
Aspartic Acid
Anesthetics
Gases
Glutamate Receptors
Xenopus
aspartic acid receptor
Oocytes
Cerebrospinal Fluid
Protons
Sodium

Keywords

  • Anaesthesia
  • Anaesthetic gases
  • Carbon dioxide
  • Hypercapnia
  • Ion channels
  • N-methyl-D-aspartate
  • pH
  • Receptor pharmacology

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Carbon dioxide negatively modulates N-methyl-d-aspartate receptors. / Brosnan, Robert J; Pham, T. L.

In: British Journal of Anaesthesia, Vol. 101, No. 5, 11.2008, p. 673-679.

Research output: Contribution to journalArticle

@article{e9052d8220c3403dbabe76c40d77ce68,
title = "Carbon dioxide negatively modulates N-methyl-d-aspartate receptors",
abstract = "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 NaHCO 3. 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",
author = "Brosnan, {Robert J} and Pham, {T. L.}",
year = "2008",
month = "11",
doi = "10.1093/bja/aen266",
language = "English (US)",
volume = "101",
pages = "673--679",
journal = "British Journal of Anaesthesia",
issn = "0007-0912",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Carbon dioxide negatively modulates N-methyl-d-aspartate receptors

AU - Brosnan, Robert J

AU - Pham, T. L.

PY - 2008/11

Y1 - 2008/11

N2 - 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 NaHCO 3. 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.

AB - 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 NaHCO 3. 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.

KW - Anaesthesia

KW - Anaesthetic gases

KW - Carbon dioxide

KW - Hypercapnia

KW - Ion channels

KW - N-methyl-D-aspartate

KW - pH

KW - Receptor pharmacology

UR - http://www.scopus.com/inward/record.url?scp=54249116309&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54249116309&partnerID=8YFLogxK

U2 - 10.1093/bja/aen266

DO - 10.1093/bja/aen266

M3 - Article

C2 - 18791188

AN - SCOPUS:54249116309

VL - 101

SP - 673

EP - 679

JO - British Journal of Anaesthesia

JF - British Journal of Anaesthesia

SN - 0007-0912

IS - 5

ER -