Potent σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo

Anish Bhardwaj, Masahiko Sawada, Edythe D. London, Raymond C. Koehler, Richard J. Traystman, Jeffrey R. Kirsch

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background and Purpose - σ-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that σ-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo. Methods - Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 μmol/L [14C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L- nitroarginine (L-NNA); the σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective σ1-receptor antagonist 1- (cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [14C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production. Results - After a 3-hour loading period with [14C]L-arginine, addition of 1 mmol/L NMDA increased [14C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L- NNA and PPBP. Perfusion of 1 mmol/L of the σ1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [14C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [14C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [14C]L-citrulline recovery in the presence of MK-801. Conclusions - These data indicate that a σ1- receptor ligand attenuates basal as well as NMDA-evoked NO production: Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the σ1-receptor. Attenuated NO production by σ1- receptor agonists provides one possible mechanism for focal ischemic neuroprotection.

Original languageEnglish (US)
Pages (from-to)2404-2411
Number of pages8
JournalStroke
Volume29
Issue number11
StatePublished - 1998
Externally publishedYes

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N-Methylaspartate
Nitric Oxide
Ligands
Citrulline
Dizocilpine Maleate
Cerebrospinal Fluid
N-Methyl-D-Aspartate Receptors
Arginine
Perfusion
4-phenyl-1-(4-phenylbutyl)piperidine
Nitroarginine
Microdialysis
Wounds and Injuries
Halothane
Drug Combinations
Wistar Rats

Keywords

  • Excitotoxicity
  • Ligands
  • Microdialysis
  • Nitric oxide
  • Rats
  • Receptors, sigma

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Bhardwaj, A., Sawada, M., London, E. D., Koehler, R. C., Traystman, R. J., & Kirsch, J. R. (1998). Potent σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo. Stroke, 29(11), 2404-2411.

Potent σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo. / Bhardwaj, Anish; Sawada, Masahiko; London, Edythe D.; Koehler, Raymond C.; Traystman, Richard J.; Kirsch, Jeffrey R.

In: Stroke, Vol. 29, No. 11, 1998, p. 2404-2411.

Research output: Contribution to journalArticle

Bhardwaj, A, Sawada, M, London, ED, Koehler, RC, Traystman, RJ & Kirsch, JR 1998, 'Potent σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo', Stroke, vol. 29, no. 11, pp. 2404-2411.
Bhardwaj, Anish ; Sawada, Masahiko ; London, Edythe D. ; Koehler, Raymond C. ; Traystman, Richard J. ; Kirsch, Jeffrey R. / Potent σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo. In: Stroke. 1998 ; Vol. 29, No. 11. pp. 2404-2411.
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abstract = "Background and Purpose - σ-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that σ-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo. Methods - Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 μmol/L [14C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L- nitroarginine (L-NNA); the σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective σ1-receptor antagonist 1- (cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [14C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production. Results - After a 3-hour loading period with [14C]L-arginine, addition of 1 mmol/L NMDA increased [14C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L- NNA and PPBP. Perfusion of 1 mmol/L of the σ1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [14C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [14C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [14C]L-citrulline recovery in the presence of MK-801. Conclusions - These data indicate that a σ1- receptor ligand attenuates basal as well as NMDA-evoked NO production: Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the σ1-receptor. Attenuated NO production by σ1- receptor agonists provides one possible mechanism for focal ischemic neuroprotection.",
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AU - Bhardwaj, Anish

AU - Sawada, Masahiko

AU - London, Edythe D.

AU - Koehler, Raymond C.

AU - Traystman, Richard J.

AU - Kirsch, Jeffrey R.

PY - 1998

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N2 - Background and Purpose - σ-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that σ-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo. Methods - Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 μmol/L [14C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L- nitroarginine (L-NNA); the σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective σ1-receptor antagonist 1- (cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [14C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production. Results - After a 3-hour loading period with [14C]L-arginine, addition of 1 mmol/L NMDA increased [14C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L- NNA and PPBP. Perfusion of 1 mmol/L of the σ1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [14C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [14C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [14C]L-citrulline recovery in the presence of MK-801. Conclusions - These data indicate that a σ1- receptor ligand attenuates basal as well as NMDA-evoked NO production: Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the σ1-receptor. Attenuated NO production by σ1- receptor agonists provides one possible mechanism for focal ischemic neuroprotection.

AB - Background and Purpose - σ-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that σ-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo. Methods - Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 μmol/L [14C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L- nitroarginine (L-NNA); the σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective σ1-receptor antagonist 1- (cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [14C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production. Results - After a 3-hour loading period with [14C]L-arginine, addition of 1 mmol/L NMDA increased [14C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L- NNA and PPBP. Perfusion of 1 mmol/L of the σ1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [14C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [14C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [14C]L-citrulline recovery in the presence of MK-801. Conclusions - These data indicate that a σ1- receptor ligand attenuates basal as well as NMDA-evoked NO production: Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the σ1-receptor. Attenuated NO production by σ1- receptor agonists provides one possible mechanism for focal ischemic neuroprotection.

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KW - Ligands

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