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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCardiovascular

Enhanced Vascular Neuronal Nitric-Oxide Synthase-Derived Nitric-Oxide Production Underlies the Pressor Response Caused by Peripheral N-Methyl-d-Aspartate Receptor Activation in Conscious Rats

Marie A. McGee and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 461-471; DOI: https://doi.org/10.1124/jpet.112.194464
Marie A. McGee
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Abdel A. Abdel-Rahman
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Abstract

Although the N-methyl-d-aspartate (NMDA) receptor (NMDAR) obligatory unit NMDAR1 is expressed in the vasculature and myocardium, the impact of peripheral NMDAR activation on blood pressure (BP) has received little attention. We demonstrate, for the first time, dose-related pressor responses elicited by systemic NMDA (125, 250, 500, and 1000 μg/kg) in conscious rats. The pressor response was peripheral NMDAR-mediated because: 1) it persisted after ganglion blockade (hexamethonium; 5 mg/kg i.v.); 2) it was attenuated by the selective NMDAR blocker dl-2-amino-5-phosphonopentanoic acid (5 mg/kg, i.v.) or the glycine/NMDAR antagonist R-(+)-3-amino-1-hydroxypyrrolid-2-one [R-(+)-HA-966; 10 mg/kg i.v.]; and 3) NMDA (1.25–10 mM) increased contractile force of rat aorta in vitro. It is noteworthy that ex vivo studies revealed enhanced nitric oxide (NO) and reactive oxygen species (ROS) generation in vascular tissues collected at the peak of the NMDAR-mediated pressor response. Pharmacological, ex vivo, and in vitro findings demonstrated attenuation of the NMDAR-mediated increases in BP and vascular NO and ROS by the nonselective NO synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester hydrochloride (10 mg/kg i.v.) or the neuronal NOS (nNOS) inhibitor Nω-propyl-l-arginine hydrochloride (150 μg/kg i.p.) but not by the endothelial NOS inhibitor N5-(1-iminoethyl)-l-ornithine (4 or 10 mg/kg i.v.). Furthermore, R-(+)-HA-966 attenuated NMDA-evoked generation of vascular NO and ROS. The findings suggest a pivotal role for enhanced vascular nNOS-derived NO in ROS generation and in the subsequent pressor response elicited by peripheral NMDAR in conscious rats.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.194464.

  • ABBREVIATIONS:

    NMDA
    N-methyl-d-aspartate
    NMDAR
    NMDA receptor
    AP-5
    dl-2-amino-5-phosphonopentanoic acid
    BP
    blood pressure
    CNS
    central nervous system
    DAF-FM
    4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate
    DCF
    2′,7′-dichlorofluorescein
    HR
    heart rate
    NO
    nitric oxide
    NOS
    NO synthase
    eNOS
    endothelial NOS
    iNOS
    inducible NOS
    nNOS
    neuronal NOS
    l-NAME
    Nω-nitro-l-arginine methyl ester
    l-NIO
    N5-(1-iminoethyl)-l-ornithine
    MAP
    mean arterial pressure
    Nox
    NADPH oxidase
    NOx
    nitrite/nitrate
    NPLA
    Nω-propyl-l-arginine
    PE
    phenylephrine
    R-(+)-HA-966
    R-(+)-3-amino-1-hydroxypyrrolid-2-one
    RFU
    relative fluorescence units
    ROS
    reactive oxygen species.

  • Received March 16, 2012.
  • Accepted May 9, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleCardiovascular

Peripheral NMDAR Mediates Pressor Response in Conscious Rats

Marie A. McGee and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 461-471; DOI: https://doi.org/10.1124/jpet.112.194464

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Research ArticleCardiovascular

Peripheral NMDAR Mediates Pressor Response in Conscious Rats

Marie A. McGee and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 461-471; DOI: https://doi.org/10.1124/jpet.112.194464
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