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Research ArticleEndocrine and Diabetes

Cerebral Myogenic Reactivity and Blood Flow in Type 2 Diabetic Rats: Role of Peroxynitrite in Hypoxia-Mediated Loss of Myogenic Tone

Aisha I. Kelly-Cobbs, Roshini Prakash, Maha Coucha, Robert A. Knight, Weiguo Li, Safia N. Ogbi, Maribeth Johnson and Adviye Ergul
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 407-415; DOI: https://doi.org/10.1124/jpet.111.191296
Aisha I. Kelly-Cobbs
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Roshini Prakash
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Maha Coucha
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Robert A. Knight
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Weiguo Li
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Safia N. Ogbi
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Maribeth Johnson
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Adviye Ergul
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Abstract

Dysregulation of cerebral vascular function and, ultimately, cerebral blood flow (CBF) may contribute to complications such as stroke and cognitive decline in diabetes. We hypothesized that 1) diabetes-mediated neurovascular and myogenic dysfunction impairs CBF and 2) under hypoxic conditions, cerebral vessels from diabetic rats lose myogenic properties because of peroxynitrite (ONOO−)-mediated nitration of vascular smooth muscle (VSM) actin. Functional hyperemia, the ability of blood vessels to dilate upon neuronal stimulation, and myogenic tone of isolated middle cerebral arteries (MCAs) were assessed as indices of neurovascular and myogenic function, respectively, in 10- to 12-week control and type 2 diabetic Goto-Kakizaki rats. In addition, myogenic behavior of MCAs, nitrotyrosine (NY) levels, and VSM actin content were measured under normoxic and hypoxic [oxygen glucose deprivation (OGD)] conditions with and without the ONOO− decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl) prophyrinato iron (III), chloride (FeTPPs). The percentage of myogenic tone was higher in diabetes, and forced dilation occurred at higher pressures. Functional hyperemia was impaired. Consistent with these findings, baseline CBF was lower in diabetes. OGD reduced the percentage of myogenic tone in both groups, and FeTPPs restored it only in diabetes. OGD increased VSM NY in both groups, and although FeTPPs restored basal levels, it did not correct the reduced filamentous/globular (F/G) actin ratio. Acute alterations in VSM ONOO− levels may contribute to hypoxic myogenic dysfunction, but this cannot be solely explained by the decreased F/G actin ratio due to actin nitration, and mechanisms may differ between control and diabetic animals. Our findings also demonstrate that diabetes alters the ability of cerebral vessels to regulate CBF under basal and hypoxic conditions.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant F31-NS066746] (to A.I.K.-C.). Additional support was provided in part by a Veteran's Affairs Merit Award [BX000347]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS054688]; and an American Heart Association Established Investigator Award [0740002N] (to A.E.). A.E. is a research pharmacologist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia.

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

    http://dx.doi.org/10.1124/jpet.111.191296.

  • ABBREVIATIONS:

    T2D
    type 2 diabetes
    FeTPPs
    5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III), chloride
    CBF
    cerebral blood flow
    OGD
    oxygen glucose deprivation
    MCA
    middle cerebral artery
    PCA
    posterior cerebral artery
    ROI
    region of interest
    LD
    lumen diameter
    MT
    media thickness
    VSM
    vascular smooth muscle
    STZ
    streptozotocin
    GK
    Goto-Kakizaki
    OD
    outer diameter
    NO
    nitric oxide.

  • Received December 26, 2011.
  • Accepted May 7, 2012.
  • U.S. Government work not protected by U.S. copyright
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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 ArticleEndocrine and Diabetes

Cerebrovascular Reactivity and Oxidative Stress in Diabetes

Aisha I. Kelly-Cobbs, Roshini Prakash, Maha Coucha, Robert A. Knight, Weiguo Li, Safia N. Ogbi, Maribeth Johnson and Adviye Ergul
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 407-415; DOI: https://doi.org/10.1124/jpet.111.191296

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Research ArticleEndocrine and Diabetes

Cerebrovascular Reactivity and Oxidative Stress in Diabetes

Aisha I. Kelly-Cobbs, Roshini Prakash, Maha Coucha, Robert A. Knight, Weiguo Li, Safia N. Ogbi, Maribeth Johnson and Adviye Ergul
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 407-415; DOI: https://doi.org/10.1124/jpet.111.191296
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