Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats

Anish Bhardwaj, Frances J. Northington, Rebecca N. Ichord, Daniel F. Hanley, Richard J. Traystman, Raymond C. Koehler

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Background and Purpose: Glutamate receptor activation can stimulate nitric oxide (NO) production and possibly play a role in long-term potentiation and excitotoxic-mediated injury. We studied the differential effect of agonist-induced activation of ion channel linked N-methyl-D- aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtypes on NO production in vivo in rat hippocampus. We also studied whether dantrolene, a ryanodine calcium channel inhibitor previously shown to attenuate metabotropic glutamate receptor stimulation of NO production, also attenuated ionotropic glutamate receptor mediated stimulation of NO production. Methods: Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of pentobarbital- anesthetized adult Sprague-Dawley rats and were perfused for 5 hours with artificial cerebrospinal fluid (CSF) containing 3 μmol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 13 groups of rats, increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with no additional drugs versus combinations of NMDA, AMPA, the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME), the noncompetitive glutamate receptor blocker MK-801, the AMPA receptor antagonist 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX), and dantrolene. Results: Recovery of [14C]L-citrulline during perfusion with artificial CSF progressively increased to 272-±73 fmol/min (±SEM) over 5 hours. Contralateral perfusion with 1 mmol/L L-NAME inhibited [14C]L-citrulline recovery. Perfusion with 1 mmol/L MK-801 or I mmol/L CNQX reduced [14C]L-citrulline recovery compared with contralateral perfusion with CSF alone. Perfusion with 1 mmol/L NMDA enhanced [14C]L-citrulline recovery, and this enhancement was attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. Perfusion with 1 mmol/L AMPA enhanced [14C]L-citrulline recovery, and this enhancement was also attenuated by L-NAME, MK801, and CNQX but not by dantrolene. Conclusions: Through an indirect method of assessing NO production in vivo, results with MK-801 and CNQX indicate that NMDA and AMPA receptor activation contribute to basal NO production in the rat hippocampus. Enhanced NO production with NMDA and AMPA agonists appears to involve a complex neuronal interaction because the effect of NMDA was attenuated by both MK-801 and CNQX and because the effect of AMPA was attenuated by both CNQX and MK-801. In contrast to metabotropic glutamate receptor activation, release of calcium from intracellular ryanodine calcium channels does not appear to be a prominent mediator of ionotropic glutamate receptor stimulation of NO production.

Original languageEnglish (US)
Pages (from-to)850-857
Number of pages8
JournalStroke
Volume28
Issue number4
StatePublished - Apr 1997
Externally publishedYes

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Ionotropic Glutamate Receptors
Citrulline
Nitric Oxide
Dizocilpine Maleate
N-Methylaspartate
Dantrolene
Perfusion
NG-Nitroarginine Methyl Ester
Cerebrospinal Fluid
Ryanodine
Hippocampus
Metabotropic Glutamate Receptors
Glutamate Receptors
Calcium Channels
6-Cyano-7-nitroquinoxaline-2,3-dione
Long-Term Potentiation
Microdialysis
Pentobarbital
Drug Combinations
bucide

Keywords

  • hippocampus
  • N-methyl-D-aspartate
  • nitric oxide
  • rats

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Bhardwaj, A., Northington, F. J., Ichord, R. N., Hanley, D. F., Traystman, R. J., & Koehler, R. C. (1997). Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats. Stroke, 28(4), 850-857.

Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats. / Bhardwaj, Anish; Northington, Frances J.; Ichord, Rebecca N.; Hanley, Daniel F.; Traystman, Richard J.; Koehler, Raymond C.

In: Stroke, Vol. 28, No. 4, 04.1997, p. 850-857.

Research output: Contribution to journalArticle

Bhardwaj, A, Northington, FJ, Ichord, RN, Hanley, DF, Traystman, RJ & Koehler, RC 1997, 'Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats', Stroke, vol. 28, no. 4, pp. 850-857.
Bhardwaj A, Northington FJ, Ichord RN, Hanley DF, Traystman RJ, Koehler RC. Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats. Stroke. 1997 Apr;28(4):850-857.
Bhardwaj, Anish ; Northington, Frances J. ; Ichord, Rebecca N. ; Hanley, Daniel F. ; Traystman, Richard J. ; Koehler, Raymond C. / Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats. In: Stroke. 1997 ; Vol. 28, No. 4. pp. 850-857.
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T1 - Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats

AU - Bhardwaj, Anish

AU - Northington, Frances J.

AU - Ichord, Rebecca N.

AU - Hanley, Daniel F.

AU - Traystman, Richard J.

AU - Koehler, Raymond C.

PY - 1997/4

Y1 - 1997/4

N2 - Background and Purpose: Glutamate receptor activation can stimulate nitric oxide (NO) production and possibly play a role in long-term potentiation and excitotoxic-mediated injury. We studied the differential effect of agonist-induced activation of ion channel linked N-methyl-D- aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtypes on NO production in vivo in rat hippocampus. We also studied whether dantrolene, a ryanodine calcium channel inhibitor previously shown to attenuate metabotropic glutamate receptor stimulation of NO production, also attenuated ionotropic glutamate receptor mediated stimulation of NO production. Methods: Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of pentobarbital- anesthetized adult Sprague-Dawley rats and were perfused for 5 hours with artificial cerebrospinal fluid (CSF) containing 3 μmol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 13 groups of rats, increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with no additional drugs versus combinations of NMDA, AMPA, the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME), the noncompetitive glutamate receptor blocker MK-801, the AMPA receptor antagonist 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX), and dantrolene. Results: Recovery of [14C]L-citrulline during perfusion with artificial CSF progressively increased to 272-±73 fmol/min (±SEM) over 5 hours. Contralateral perfusion with 1 mmol/L L-NAME inhibited [14C]L-citrulline recovery. Perfusion with 1 mmol/L MK-801 or I mmol/L CNQX reduced [14C]L-citrulline recovery compared with contralateral perfusion with CSF alone. Perfusion with 1 mmol/L NMDA enhanced [14C]L-citrulline recovery, and this enhancement was attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. Perfusion with 1 mmol/L AMPA enhanced [14C]L-citrulline recovery, and this enhancement was also attenuated by L-NAME, MK801, and CNQX but not by dantrolene. Conclusions: Through an indirect method of assessing NO production in vivo, results with MK-801 and CNQX indicate that NMDA and AMPA receptor activation contribute to basal NO production in the rat hippocampus. Enhanced NO production with NMDA and AMPA agonists appears to involve a complex neuronal interaction because the effect of NMDA was attenuated by both MK-801 and CNQX and because the effect of AMPA was attenuated by both CNQX and MK-801. In contrast to metabotropic glutamate receptor activation, release of calcium from intracellular ryanodine calcium channels does not appear to be a prominent mediator of ionotropic glutamate receptor stimulation of NO production.

AB - Background and Purpose: Glutamate receptor activation can stimulate nitric oxide (NO) production and possibly play a role in long-term potentiation and excitotoxic-mediated injury. We studied the differential effect of agonist-induced activation of ion channel linked N-methyl-D- aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtypes on NO production in vivo in rat hippocampus. We also studied whether dantrolene, a ryanodine calcium channel inhibitor previously shown to attenuate metabotropic glutamate receptor stimulation of NO production, also attenuated ionotropic glutamate receptor mediated stimulation of NO production. Methods: Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of pentobarbital- anesthetized adult Sprague-Dawley rats and were perfused for 5 hours with artificial cerebrospinal fluid (CSF) containing 3 μmol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 13 groups of rats, increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with no additional drugs versus combinations of NMDA, AMPA, the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME), the noncompetitive glutamate receptor blocker MK-801, the AMPA receptor antagonist 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX), and dantrolene. Results: Recovery of [14C]L-citrulline during perfusion with artificial CSF progressively increased to 272-±73 fmol/min (±SEM) over 5 hours. Contralateral perfusion with 1 mmol/L L-NAME inhibited [14C]L-citrulline recovery. Perfusion with 1 mmol/L MK-801 or I mmol/L CNQX reduced [14C]L-citrulline recovery compared with contralateral perfusion with CSF alone. Perfusion with 1 mmol/L NMDA enhanced [14C]L-citrulline recovery, and this enhancement was attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. Perfusion with 1 mmol/L AMPA enhanced [14C]L-citrulline recovery, and this enhancement was also attenuated by L-NAME, MK801, and CNQX but not by dantrolene. Conclusions: Through an indirect method of assessing NO production in vivo, results with MK-801 and CNQX indicate that NMDA and AMPA receptor activation contribute to basal NO production in the rat hippocampus. Enhanced NO production with NMDA and AMPA agonists appears to involve a complex neuronal interaction because the effect of NMDA was attenuated by both MK-801 and CNQX and because the effect of AMPA was attenuated by both CNQX and MK-801. In contrast to metabotropic glutamate receptor activation, release of calcium from intracellular ryanodine calcium channels does not appear to be a prominent mediator of ionotropic glutamate receptor stimulation of NO production.

KW - hippocampus

KW - N-methyl-D-aspartate

KW - nitric oxide

KW - rats

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