Show simple item record

dc.contributor.authorPuttabyatappa, Yashoda
dc.date.accessioned2020-10-15T17:19:46Z
dc.date.available2020-10-15T17:19:46Z
dc.date.issued2010
dc.identifier.urien
dc.identifier.urihttp://hdl.handle.net/10675.2/623593
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus.
dc.description.abstractPrescription 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.en_US
dc.language.isoen_USen_US
dc.publisherMedical College of Georgiaen_US
dc.relation.urlhttps://search.proquest.com/docview/863629357?accountid=12365
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en_US
dc.subjectTestosteroneen_US
dc.subjectvascular reactivityen_US
dc.subjectperoxynitriteen_US
dc.subjectsuperoxideen_US
dc.subjectnitric oxideen_US
dc.subjectryanodineen_US
dc.subjectBKCa channelen_US
dc.titleAcute non-genomic effects of testosterone in mesenteric microvessels: Role of peroxynitrite and prostaglandin E2en_US
dc.typeDissertationen_US
dc.contributor.departmentDepartment of Pharmacology and Toxicologyen_US
dc.contributor.corporatenameSchool of Graduate Studiesen_US
dc.description.advisorWhite, Richard E
dc.description.degreeDoctor of Philosophy with a Major in Pharmacologyen_US
dc.description.committeeCaldwell, William
dc.description.committeeBarman, Scott
dc.description.committeeErgul, Adviye
dc.description.committeeEl-Remessy, Azza
dc.embargoen
refterms.dateFOA2020-10-15T17:19:47Z


Files in this item

Thumbnail
Name:
Puttabyatappa_Yashoda_PhD_2011.pdf
Size:
3.001Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record