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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Type 1 Diabetes-Induced Hyper-Responsiveness to 5-Hydroxytryptamine in Rat Pulmonary Arteries via Oxidative Stress and Induction of Cyclooxygenase-2

Jose G. Lopez-Lopez, Javier Moral-Sanz, Giovanna Frazziano, Maria J. Gomez-Villalobos, Laura Moreno, Carmen Menendez, Jorge Flores-Hernandez, Jose A. Lorente, Angel Cogolludo and Francisco Perez-Vizcaino
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 400-407; DOI: https://doi.org/10.1124/jpet.111.179515
Jose G. Lopez-Lopez
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Javier Moral-Sanz
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Giovanna Frazziano
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Maria J. Gomez-Villalobos
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Laura Moreno
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Carmen Menendez
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Jorge Flores-Hernandez
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Jose A. Lorente
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Angel Cogolludo
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Francisco Perez-Vizcaino
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Abstract

Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension.

Footnotes

  • This work was supported by the Ministerio de Ciencia e Innovación [Grants SAF2008-03948, SAF2010-22066-C02-02, AGL2007-66108] and Mutua Madrileña.

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

    doi:10.1124/jpet.111.179515.

  • ABBREVIATIONS:

    PAH
    pulmonary arterial hypertension
    5-HT
    5-hydroxytryptamine (serotonin)
    BMPR2
    bone morphogenetic protein receptor type 2
    BW
    body weight
    COX
    cyclooxygenase
    Emax
    maximal drug effect
    KV
    voltage-gated potassium channel
    LV
    left ventricle
    PA
    pulmonary artery
    S
    septum
    SAP
    systemic arterial pressure
    RV
    right ventricle
    RVSP
    right ventricular systolic pressure
    SOD
    superoxide dismutase
    TXA2
    thromboxane A2
    NS-398
    N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide
    U46619
    (Z)-7-[(1S,3S,4S)-3-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxabicyclo[2.2.1]heptan-2-yl]hept-5-enoic acid
    l-NAME
    Nω-nitro-l-arginine methyl ester
    SC236
    4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide
    TP
    thromboxane prostanoid
    ROS
    reactive oxygen species.

  • Received January 17, 2011.
  • Accepted April 25, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Type 1 Diabetes-Induced Hyper-Responsiveness to 5-Hydroxytryptamine in Rat Pulmonary Arteries via Oxidative Stress and Induction of Cyclooxygenase-2

Jose G. Lopez-Lopez, Javier Moral-Sanz, Giovanna Frazziano, Maria J. Gomez-Villalobos, Laura Moreno, Carmen Menendez, Jorge Flores-Hernandez, Jose A. Lorente, Angel Cogolludo and Francisco Perez-Vizcaino
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 400-407; DOI: https://doi.org/10.1124/jpet.111.179515

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Type 1 Diabetes-Induced Hyper-Responsiveness to 5-Hydroxytryptamine in Rat Pulmonary Arteries via Oxidative Stress and Induction of Cyclooxygenase-2

Jose G. Lopez-Lopez, Javier Moral-Sanz, Giovanna Frazziano, Maria J. Gomez-Villalobos, Laura Moreno, Carmen Menendez, Jorge Flores-Hernandez, Jose A. Lorente, Angel Cogolludo and Francisco Perez-Vizcaino
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 400-407; DOI: https://doi.org/10.1124/jpet.111.179515
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