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This dissertation, Modulation of Vascular Contraction by Testosterone in Porcine Coronary Artery by Pik-shan, Cynthia, Chan, 陳碧珊, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Modulation of vascular contraction by testosterone in porcine coronary artery Submitted by Cynthia Pik Shan Chan for the degree of Master of Philosophy at the University of Hong Kong in September, 2007 Men have a higher incidence of coronary heart disease than premenopausal women at similar age. This has led to the hypothesis that testosterone may increase the risk of coronary heart disease in men. However, there is no general consensus on how testosterone may increase the risk of coronary heart disease. Since the effect and the mechanism of testosterone on the vascular functions have not been fully elucidated, the objective of my study is to investigate the relationship between testosterone and vascular function. Acute expose to testosterone enhanced contractions in both isolated endothelium- intact or endothelium-denuded porcine coronary arteries in vitro. The enhanced agonist-induced contraction by testosterone was endothelium-independent. Effect of testosterone was blocked by the adenylyl cyclase antagonist, SQ 22536, the competitive antagonist of adenosine-3', 5'-cyclic monophosphate (cAMP), Rp-8-Br- cAMPS and protein kinase A antagonist, KT 5720. Effect of testosterone was not altered when the protein kinase G antagonist, KT 5823 or competitive antagonist of guanosine-3', 5'-cyclic monophosphate (cGMP), Rp-8-Br-cGMPS was present. These results suggest that testosterone modulates vascular tone via adenylyl cyclase and the iicAMP second messenger signaling pathway. These results also suggest that the protein kinase G and cGMP pathway was not involved. Effect of testosterone on the enhancement of U46619-induced contractions was altered by G protein inhibitors, pertussis toxin and NF 023, as well as by the G γi γs protein inhibitor, NF 449. At the moment, it is not clear how both G and G proteins γs γi are both involved in the effect of testosterone to enhance contraction. In addition, testosterone-mediated effect on enhanced contraction was blocked when the Rho kinase inhibitor, Y-27632, was present. This suggests that testosterone may modulate the vascular reactivity via the Rho kinase signaling pathway. Preliminary results showed U46619 increased Rho kinase expression and activity in porcine coronary rings and the presence of testosterone further increased Rho kinase expression and activity. Thus the testosterone-mediated enhancement of contraction may be via an increase in the production of cAMP which then activates the Rho kinase to regulate the vascular tone. In conclusions, this study has revealed the signaling pathway for the acute in vitro action of testosterone in porcine coronary arteries, thus contributing new knowledge about the action of the male sex hormone in the regulation of the vascular system. (372 words) iii DOI: 10.5353/th_b3955812 Subjects: Coronary arteriesTestosteroneAndrogens - PathophysiologyCoronary heart disease

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