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Research ArticleCardiovascular

Peroxynitrite Mediates Testosterone-Induced Vasodilation of Microvascular Resistance Vessels

Yashoda Puttabyatappa, John N. Stallone, Adviye Ergul, Azza B. El-Remessy, Sanjiv Kumar, Stephen Black, Maribeth Johnson, Mary P. Owen and Richard E. White
Journal of Pharmacology and Experimental Therapeutics April 2013, 345 (1) 7-14; DOI: https://doi.org/10.1124/jpet.112.201947
Yashoda Puttabyatappa
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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John N. Stallone
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Adviye Ergul
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Azza B. El-Remessy
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Sanjiv Kumar
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Stephen Black
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Maribeth Johnson
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Mary P. Owen
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Richard E. White
Department of Pharmacology & Toxicology (Y.P.), the Vascular Biology Center (S.B., S.K.), the Department of Physiology (A.E.), and the Department of Biostatistics (M.J.), Georgia Health Sciences University, Augusta, Georgia; Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (A.B.E.-R.); Women’s Health Center and the Department of Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (J.N.S.); and Department of Basic Sciences, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, Georgia (M.P.O., R.E.W.)
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Abstract

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.

Footnotes

    • Received November 16, 2012.
    • Accepted December 13, 2012.
  • This work was supported in part by grants from the National Institutes of Health [Grants HL080402 (to J.N.S. and R.E.W.), NS070239 (to A.E.), EY022408 (to A.B.E.), HL06190, and HL67841 (to S.B.)]; Juvenile Diabetes Research Foundation [JDRF 2-2008-149] (to A.B.E.); Center for Chronic Disorders of Aging, endowed by the Osteopathic Heritage Foundation (to M.P.O.); and an American Heart Association Established Investigator Award (to A.E.).

  • dx.doi.org/10.1124/jpet.112.201947.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 1
1 Apr 2013
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Research ArticleCardiovascular

Nongenomic Testosterone Signaling in the Microvasculature

Yashoda Puttabyatappa, John N. Stallone, Adviye Ergul, Azza B. El-Remessy, Sanjiv Kumar, Stephen Black, Maribeth Johnson, Mary P. Owen and Richard E. White
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 7-14; DOI: https://doi.org/10.1124/jpet.112.201947

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Research ArticleCardiovascular

Nongenomic Testosterone Signaling in the Microvasculature

Yashoda Puttabyatappa, John N. Stallone, Adviye Ergul, Azza B. El-Remessy, Sanjiv Kumar, Stephen Black, Maribeth Johnson, Mary P. Owen and Richard E. White
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 7-14; DOI: https://doi.org/10.1124/jpet.112.201947
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