This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhardwaj, A. Articles by Faraci, F. M. Search for Related Content PubMed PubMed Citation Articles by Bhardwaj, A. Articles by Faraci, F. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE

(Stroke. 1998;29:2404-2411.)
© 1998 American Heart Association, Inc.

Original Contributions

Potent ₁-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine Modulates Basal and N-Methyl-D-Aspartate–Evoked Nitric Oxide Production In Vivo

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

From the Departments of Neurology (A.B.) and Anesthesiology and Critical Care Medicine (A.B., M.S., R.C.K., R.J.T., J.R.K.), Johns Hopkins University School of Medicine, and National Institute on Drug Abuse (E.D.L.), Baltimore, Md.

Correspondence to Anish Bhardwaj, MD, Neuroscience Critical Care Division, Meyer 8–140, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail abhardwa{at}welchlink.welch.jhu.edu

Background and Purpose—-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 -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 ₁-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective ₁-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 ₁-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 ₁-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 ₁-receptor. Attenuated NO production by ₁-receptor agonists provides one possible mechanism for focal ischemic neuroprotection.

Editorial Comment

Frank M. Faraci, PhD, Guest Editor

Department of Internal Medicine Cardiovascular Division University of Iowa College of Medicine Iowa City, Iowa

This article has been cited by other articles:

				S. Yang, N. J. Alkayed, P. D. Hurn, and J. R. Kirsch Cyclic Adenosine Monophosphate Response Element-Binding Protein Phosphorylation and Neuroprotection by 4-Phenyl-1-(4-Phenylbutyl) Piperidine (PPBP) Anesth. Analg., March 1, 2009; 108(3): 964 - 970. [Abstract] [Full Text] [PDF]

				H. Girouard, G. Wang, E. F. Gallo, J. Anrather, P. Zhou, V. M. Pickel, and C. Iadecola NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2 J. Neurosci., February 25, 2009; 29(8): 2545 - 2552. [Abstract] [Full Text] [PDF]

				S. B. Smith, J. Duplantier, Y. Dun, B. Mysona, P. Roon, P. M. Martin, and V. Ganapathy In Vivo Protection against Retinal Neurodegeneration by Sigma Receptor 1 Ligand (+)-Pentazocine Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 4154 - 4161. [Abstract] [Full Text] [PDF]

				Y. Dun, M. Thangaraju, P. Prasad, V. Ganapathy, and S. B. Smith Prevention of Excitotoxicity in Primary Retinal Ganglion Cells by (+)-Pentazocine, a Sigma Receptor-1 Specific Ligand Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4785 - 4794. [Abstract] [Full Text] [PDF]

				G. Jiang, B. Mysona, Y. Dun, J. P. Gnana-Prakasam, N. Pabla, W. Li, Z. Dong, V. Ganapathy, and S. B. Smith Expression, Subcellular Localization, and Regulation of Sigma Receptor in Retinal Muller Cells Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5576 - 5582. [Abstract] [Full Text] [PDF]

				K. Vagnerova, P. D. Hurn, A. Bhardwaj, and J. R. Kirsch Sigma 1 receptor agonists act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. Anesth. Analg., August 1, 2006; 103(2): 430 - 4, table of contents. [Abstract] [Full Text] [PDF]

				T. Goyagi, T. J.K. Toung, J. R. Kirsch, R. J. Traystman, R. C. Koehler, P. D. Hurn, and A. Bhardwaj Neuroprotective {kappa}-Opioid Receptor Agonist BRL 52537 Attenuates Ischemia-Evoked Nitric Oxide Production In Vivo in Rats Stroke, June 1, 2003; 34(6): 1533 - 1538. [Abstract] [Full Text] [PDF]

				T. Goyagi, A. Bhardwaj, R. C. Koehler, R. J. Traystman, P. D. Hurn, and J. R. Kirsch Potent {sigma}1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine Provides Ischemic Neuroprotection Without Altering Dopamine Accumulation In Vivo in Rats Anesth. Analg., February 1, 2003; 96(2): 532 - 538. [Abstract] [Full Text] [PDF]

				T. Goyagi, S. Goto, A. Bhardwaj, V. L. Dawson, P. D. Hurn, and J. R. Kirsch Neuroprotective Effect of {{sigma}}1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine (PPBP) Is Linked to Reduced Neuronal Nitric Oxide Production Stroke, July 1, 2001; 32(7): 1613 - 1620. [Abstract] [Full Text] [PDF]

				A. Bhardwaj, F. J. Northington, J. R. Carhuapoma, J. R. Falck, D. R. Harder, R. J. Traystman, and R. C. Koehler P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-D-aspartate Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1616 - H1624. [Abstract] [Full Text] [PDF]

				I. Harukuni, A. Bhardwaj, A. B. Shaivitz, A. C. DeVries, E. D. London, P. D. Hurn, R. J. Traystman, J. R. Kirsch, and F. M. Faraci {sigma}1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl)-Piperidine Affords Neuroprotection From Focal Ischemia With Prolonged Reperfusion • Editorial Comment Stroke, April 1, 2000; 31(4): 976 - 982. [Abstract] [Full Text] [PDF]

				T. J. Toung, A. Bhardwaj, V. L. Dawson, T. M. Dawson, R. J. Traystman, P. D. Hurn, and P. H. Chan Neuroprotective FK506 Does Not Alter In Vivo Nitric Oxide Production During Ischemia and Early Reperfusion in Rats • Editorial Comment Stroke, June 1, 1999; 30(6): 1279 - 1285. [Abstract] [Full Text] [PDF]