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Research ArticleCardiovascular

Cannabidiol Improves Vasorelaxation in Zucker Diabetic Fatty Rats through Cyclooxygenase Activation

Amanda J. Wheal, Mariateresa Cipriano, Christopher J. Fowler, Michael D. Randall and Saoirse Elizabeth O’Sullivan
Journal of Pharmacology and Experimental Therapeutics November 2014, 351 (2) 457-466; DOI: https://doi.org/10.1124/jpet.114.217125
Amanda J. Wheal
Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.)
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Mariateresa Cipriano
Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.)
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Christopher J. Fowler
Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.)
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Michael D. Randall
Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.)
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Saoirse Elizabeth O’Sullivan
Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.)
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Abstract

Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. We recently showed that CBD also improves vasorelaxation in the Zucker diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect. Femoral arteries from ZDF rats and ZDF lean controls were isolated, mounted on a myograph, and incubated with CBD (10 μM) or vehicle for 2 hours. Subsequent vasorelaxant responses were measured in combination with various interventions. Prostaglandin metabolites were detected using enzyme immunoassay. Direct effects of CBD on cyclooxygenase (COX) enzyme activity were measured by oxygraph assay. CBD enhanced the maximum vasorelaxation to acetylcholine (ACh) in femoral arteries from ZDF lean rats (P < 0.01) and especially ZDF rats (P < 0.0001). In ZDF arteries, this enhancement persisted after cannabinoid receptor (CB) type 1, endothelial CB, or peroxisome proliferator–activated receptor-γ antagonism but was inhibited by CB2 receptor antagonism. CBD also uncovered a vasorelaxant response to a CB2 agonist not previously observed. The CBD-enhanced ACh response was endothelium-, nitric oxide–, and hydrogen peroxide–independent. It was, however, COX-1/2– and superoxide dismutase–dependent, and CBD enhanced the activity of both purified COX-1 and COX-2. The CBD-enhanced ACh response in the arteries was inhibited by a prostanoid EP4 receptor antagonist. Prostaglandin E2 metabolite levels were below the limits of detection, but 6-keto prostaglandin F1α was decreased after CBD incubation. These data show that CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX-1/2–derived products acting at EP4 receptors.

Footnotes

    • Received May 30, 2014.
    • Accepted September 4, 2014.
  • All animal studies were funded by Diabetes UK [Reference: 08/0003822]. C.J.F. received financial support from the Swedish Research Council [Grant No. 12158, Medicine] and the Research Funds of the Medical Faculty, Umeå University. The authors report no conflicts of interest.

  • dx.doi.org/10.1124/jpet.114.217125.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 2
1 Nov 2014
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Research ArticleCardiovascular

Mechanisms of CBD-Improved Vasorelaxation

Amanda J. Wheal, Mariateresa Cipriano, Christopher J. Fowler, Michael D. Randall and Saoirse Elizabeth O’Sullivan
Journal of Pharmacology and Experimental Therapeutics November 1, 2014, 351 (2) 457-466; DOI: https://doi.org/10.1124/jpet.114.217125

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Research ArticleCardiovascular

Mechanisms of CBD-Improved Vasorelaxation

Amanda J. Wheal, Mariateresa Cipriano, Christopher J. Fowler, Michael D. Randall and Saoirse Elizabeth O’Sullivan
Journal of Pharmacology and Experimental Therapeutics November 1, 2014, 351 (2) 457-466; DOI: https://doi.org/10.1124/jpet.114.217125
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