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Research ArticleCardiovascular

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Anusha Penumarti and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 44-53; DOI: https://doi.org/10.1124/jpet.114.216036
Anusha Penumarti
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina
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Abdel A. Abdel-Rahman
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina
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Abstract

Direct activation of the endocannabinoid receptor G protein–coupled receptor 18 (GPR18) in the rostral ventrolateral medulla (RVLM) of conscious rats by abnormal cannabidiol (Abn CBD; trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) elevates local nitric oxide (NO) and adiponectin (ADN) levels and reduces oxidative stress and blood pressure (BP). However, the molecular mechanisms for GPR18-mediated neurochemical responses, including the nitric oxide synthase isoform that generates NO, and their potential causal link to the BP reduction are not known. We hypothesized that GPR18-mediated enhancement of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and neuronal nitric oxide synthase (nNOS) phosphorylation, triggered by a reduction in cAMP, accounts for the NO/ADN-dependent reductions in RVLM oxidative stress and BP. Intra-RVLM GPR18 activation (Abn CBD; 0.4 μg) enhanced RVLM Akt, ERK1/2, and nNOS phosphorylation as well as ADN levels during the hypotensive response. Prior GPR18 blockade with O-1918 (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]benzene) produced the opposite effects and abrogated Abn CBD–evoked neurochemical and BP responses. Pharmacological inhibition of RVLM phosphoinositide 3-kinase (PI3K)/Akt (wortmannin), ERK1/2 (PD98059 [2-​(2-​amino-​3-​methoxyphenyl)-​4H-​1-​benzopyran-​4-​one]), or nNOS (Nω-propyl-l-arginine), or activation of adenylyl cyclase (forskolin) virtually abolished intra-RVLM Abn CBD–evoked hypotension and the increases in Akt, ERK1/2, and nNOS phosphorylation and in ADN levels in the RVLM. Our pharmacological and neurochemical findings support a pivotal role for PI3K, Akt, ERK1/2, nNOS, and adenylyl cyclase, via modulation of NO, ADN, and cAMP levels, in GPR18 regulation of the RVLM redox state and BP in conscious rats.

Footnotes

    • Received April 28, 2014.
    • Accepted August 5, 2014.
  • This work was supported in part by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant 2R01-AA07839-19].

  • dx.doi.org/10.1124/jpet.114.216036.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleCardiovascular

Mechanisms for Central GPR18-Mediated Hypotension

Anusha Penumarti and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 44-53; DOI: https://doi.org/10.1124/jpet.114.216036

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Research ArticleCardiovascular

Mechanisms for Central GPR18-Mediated Hypotension

Anusha Penumarti and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 44-53; DOI: https://doi.org/10.1124/jpet.114.216036
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