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This dissertation, Endothelium-dependent Contractions in Rodent Aortae by Hoi-ching, Eva, Tang, 鄧凱澄, 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 Endothelium-dependent contractions in rodent aortae Submitted by Eva Hoi Ching Tang For the degree of Doctor of Philosophy at the University of Hong Kong in August 2007 The endothelial cells control the tone of the underlying vascular smooth muscle by releasing vasoactive substances. Endothelium-derived relaxing factors (EDRF), in particular nitric oxide have received considerable attention, but much less are known about the ability of the endothelial cells to release endothelium-derived contracting factors (EDCF). The purpose of this thesis was to define the mechanisms underlying the release of EDCF, to explore the regulation of EDCF release and to determine the cellular modulations that take place which intensify endothelium-dependent contractions in arteries of hypertensive animals. The experiments were performed on aortae of rats and mice. Isometric tension measurements, real-time polymerase chain reaction, immunohistochemistry, Western blotting and confocal microscopy were performed. The findings demonstrated that the release of EDCF is modulated negatively by nitric oxide in an acute manner through functional antagonism or in a persistent manner through a cyclic guanosine monophosphate-dependent mechanism. The data also revealed that the precise sequence of events that occurs during endothelium-dependent contractions first requires an accumulation of calcium, which then leads to the preferential activation of endothelial cyclooxygenase-1 (COX-1), rather than the cyclooxygenase-2 (COX-2) isoform, leading to the production of iEDCF. EDCF is likely to consist of two components: 1) prostanoids (including endoperoxides, prostacyclin, thromboxane A, and prostaglandin E ) and 2) reactive 2 2 oxygen species. The former directly activate thromboxane/prostaglandin endoperoxide (TP) receptors of the vascular smooth muscle cells which leads to their contraction, while the latter first stimulate the cyclooxygenase in the smooth muscle with subsequent stimulation of the TP receptors by the produced prostanoids. Dysfunction in calcium handling is the leading causal factor for the exacerbated occurrence of endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat (SHR). The observed increased expression of endothelial COX-1, prostacyclin synthase, thromboxane synthase and enhanced TP receptors sensitivity are no prerequisites for, but intensify the magnitude of endothelium-dependent contractions. The prostaglandin E receptor subtype 3 (EP3) is the dominant prostanoid receptor subtype and its expression is greatly up-regulated in the aorta of the SHR. However, the lack of selective prostaglandin E receptor (EP) antagonists has hindered the demonstration of its direct involvement in endothelium-dependent contractions. Selective TP receptor antagonists are extremely effective in preventing endothelium- dependent contractions in vitro which highlights the prospective use of such drugs in correcting the imbalanced release of endothelium-derived vasoactive substances that accompany vascular disease. Word count: 383 ii DOI: 10.5353/th_b3955844 Subjects: EndothelinsArteries - PhysiologyRodents - Physiology

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