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Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition

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Abstract

Deterioration of vascular reactivity plays a pivotal role in vascular complications. Pentoxifylline (PTX) is a well-tolerated drug used to treat vascular insufficiency. We investigated the protective effect of PTX against vascular impairment in insulin resistance. Insulin resistance was induced by fructose (10%) in drinking water while PTX was concurrently administered (50 mg/kg-1) for 8 weeks. Serum levels of glucose, insulin, tumor necrosis factor alpha (TNF-α) were determined. Isolated aorta reactivity to phenylephrine (PE), potassium chloride (KCl), and acetylcholine (ACh) was studied, as was nitric oxide (NO) generation and histopathology. Insulin resistance was accompanied with a significant elevation in serum TNF-α level, marked leukocytes infiltration, and endothelial pyknosis. PTX inhibited insulin resistance and prevented TNF-α elevation, leukocyte infiltration and endothelial pyknosis. Vascular dysfunction was evident in insulin resistance as increased vascular contractility to PE and decreased relaxation to ACh, whereas PTX protected against this dysfunction. Notably, in vitro incubation with TNF-α (1 ng/ml-1) increased contractility to PE and decreased relaxation to ACh while concomitant PTX (1 mM) incubation partially restored response to ACh but not to PE. Furthermore, TNF-α reduced ACh-induced NO generation, whereeas PTX restored it. In conclusion, PTX protects from the impairment in vascular reactivity in insulin resistance, by a mechanism involving TNF-α inhibition.

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Abbreviations

ANOVA:

analysis of variance

NO:

nitric oxide

PTX:

pentoxifylline

PE:

phenylephrine

ROS:

reactive oxygen species

SNP:

sodium nitroprusside

TNF-α:

tumor necrosis factor alpha

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Acknowledgment

We are grateful to Dr. Mohamed Metwally, Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Egypt, for assistance in histopathology.

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Authors and Affiliations

  1. Hypertension and Vascular Center, Wake Forest University Baptist Medical Center, Winston-Salem, NC, 27157, USA

    Hany M. El-Bassossy

  2. Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    Hany M. El-Bassossy & Mona F. Mahmoud

  3. Department of Pharmacology, Faculty of Pharmacy, El Minia University, El Minia, Egypt

    Mohamed A. El-Moselhy

Authors
  1. Hany M. El-Bassossy
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  2. Mohamed A. El-Moselhy
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  3. Mona F. Mahmoud
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Correspondence to Hany M. El-Bassossy.

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El-Bassossy, H.M., El-Moselhy, M.A. & Mahmoud, M.F. Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition. Naunyn-Schmiedeberg's Arch Pharmacol 384, 277–285 (2011). https://doi.org/10.1007/s00210-011-0669-z

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  • DOI: https://doi.org/10.1007/s00210-011-0669-z

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