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    Acute non-genomic effects of testosterone in mesenteric microvessels: Role of peroxynitrite and prostaglandin E2

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    Authors
    Puttabyatappa, Yashoda
    Issue Date
    2010
    URI

    http://hdl.handle.net/10675.2/623593
    
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    Abstract
    Prescription use of testosterone (T2) has increased 500% over the past 10 years, but the effects of T2 on cardiovascular function remain highly controversial. Moreover, even less is understood regarding the effects of T2 on the resistance vasculature. The purpose of our study was to identify the cellular / molecular basis of non-genomic T2 effects on arterioles isolated from the rat mesentery. We found that T2 induced a 36.45 ± 6% maximum relaxation of (phenylephrine-contracted) microvessels at pharmacological concentrations (EC50 4.56 ± 4.4 µM). In contrast, pretreating vessels with either indomethacin (10µM) or celecoxib (10µM) to inhibit COX-2 activity increased the sensitivity of these vessels to T2 by approximately 30-fold (EC50: 7.06 ± 2.53 nM and (6.05 + 0.002) x 10-8M, respectively), thus bringing the response closer to a more physiological concentration. These studies suggest at least 2 competing/complementary mechanisms of T2 action. The response to T2 was reduced significantly by pretreatment with 10µM flutamide (androgen receptor antagonist, 16.3 ± 5.9 %), 300µM L-NAME (non-selective NOS inhibitor; 5.3 ± 1.6 %), 100µM L-NPA (nNOS-selective inhibitor; 9.28 ± 1.54%), 50nM wortmannin (PI3K inhibitor; 15.32 + 4.47 %), 1mM uric acid (peroxynitrite scavenger; 9.94 ± 3.52%), or 10μM FeTPPs (peroxynitrite scavenger; 15.81 ± 3.14%), indicating that T2-induced relaxation involves production of NO and peroxynitrite via androgen receptor-dependent activation of the PI3-Akt signaling pathway and NOS (primarily the nNOS isoform expressed in VSM). T2-induced production of reactive nitrogen and oxygen species was confirmed by both fluorescence and electron paramagnetic resonance measurements. In addition to this novel vasodilatory mechanism, our experiments indicate that these vessels stimulates production of a contractile COX-2 metabolite (PGE2), suggesting that T2-stimulated PGE2 production functions as a feedback mechanism to oppose T2-induced relaxation. In summary, we propose that mesenteric microvessels exhibit a “ying-yang” response to T2: vasodilation via peroxynitrite and contraction via PGE2, and that it is the integration between these two opposing mechanisms that determines how T2 modulates tone in the resistance vasculature.
    Affiliation
    Department of Pharmacology and Toxicology
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