Thesis (Ph.D.)--University of North Carolina at Charlotte, 2005. / Includes bibliographical references (leaves 125-139).

No description available.

Abstract Alcohol drinking may exercise both beneficial and untoward effects on the haemostatic and fibrinolytic systems. It may also predispose individuals to arterial thrombosis and trigger embolism in the brain. The aim here is to examine these problems. Methods used for evaluating platelet function were platelet aggregation and associated thromboxane B2 release, shear-induced platelet aggregation, and measurement of urinary prostaglandins. Changes in fibrinolytic system were evaluated by measuring plasminogen activator inhibitor type 1. The combined effects of alcohol drinking, physical exercise, eating a meal and circadian rhythms in healthy volunteers were examined in three experimental studies. Case-control studies were used for assessing the mechanism and etiology of ischaemic brain infarction triggered during alcohol intoxication. Alcohol drinking did not potentiate the effects of physical exercise on platelet function. Sleeping while under acute intoxication resulted in a significant activation of platelets, as shown by increased urinary excretion of a thromboxane metabolite. On the other hand, ingestion of a moderate dose of red wine seemed to attenuate platelet aggregation measured ex vivo, irrespective of whether the wine was consumed with a meal or alone. However, both red wine and a larger acute dose of alcohol in fruit juice inhibited fibrinolytic activity. In a case-control study, platelet count and function were evaluated in 426 consecutive patients hospitalized on account of acute brain infarction. Compared with the hospital-based controls, a higher than normal platelet count was observed immediately after admission. Heavy drinkers showed both higher and lower than normal platelet counts more often than the other patients with brain infarction. The changes in platelet function among the heavy drinkers reflected their recent drinking habits. Another case-control study indicated that recent heavy drinking of alcohol was an independent risk factor for cardiogenic embolism to the brain. Recent heavy drinking also seemed to predispose subjects to some other types of ischaemic brain infarction such as artery to artery embolism due to large-artery atherosclerosis and cryptogenic stroke, but these observations need to be confirmed in larger studies. In conclusion, the results show some untoward effects of acute heavy drinking of alcohol, which could contribute to the onset of brain infarction either as triggering or as predisposing factors. On the other hand, drinking of a moderate dose of red wine did not have any clear untoward effect on healthy human volunteers.

No description available.

A new prostaglandin - prostaglandin X (later renamed prostacyclin or prostaglandin I₂ (PGI₂)), was discovered by Moncada, Gryglewski, Bunting and Vane in 1976. This unstable substance was shown to be produced by vascular tissue and to be a vasodilator and the most potent endogenous inhibitor of platelet aggregation known. Because of its properties, it appeared that a lack of it may be related to the development and or maintenance of hypertension, a disorder featuring vasoconstriction and an increased tendency to arterial thrombosis. The present studies aimed to investigate this possibility using a rat model. A bioassay for prostacyclin was first perfected. This consisted of a modification of the method used by Moncada, Higgs and Vane (1977): PGI₂ released by rat aortic strips, during incubation in tris buffer, was measured by assessing the ability of the incubate to inhibit adenosine diphosphate induced aggregation of human platelets, as compared to the inhibitory effect of standard prostacyclin sodium salt. The specificity of the assay for the detection of PGI₂ was tested. The abil ity of hypertensive rat aorta to release prostacycl in was investigated in two studies. The first compared aortas of Wistar rats of the New Zealand genetically hypertensive strain (GH) with those of matched normotensive Wistar controls. In the second study, hypertension was induced by wrappi ng the ri ght kidney with surgical silk and removing the contralateral kidney. Ten weeks later, aortic generation of prostacyclin by these animals was compared with that of matched sham controls which had received identical surgical manipulation but for the application of silk to the right kidney. Contrary to expectation, in both forms of hypertension, aortas of the rats with elevated pressure produced consistently more prostacyclin than those of matched controls. In order to discover more about the relationship between elevated pressure and elevated PGI₂ production, the effect of pressure reduction with hypotensive agents on the ability of GH rat aortas to produce prostacyclin, was investigated. After pressure had been controlled within normal range for one week (achieved by oral administration of furosemide, dihydralazine and reserpine for one month), aortic PGI₂ was reduced in comparison with matched GH controls. However, the reduction was not consistent and statistical significance was not reached. Because it was subsequently reported by other workers, that some of the hypotensive agents which had been employed may effect prostaglandin levels per se, no conclusions could be drawn from this study as to any possible direct relationships between pressure and aortic prostacyclin generating capacity. A further means of reducing elevated pressure (which had no inherent effect on prostaglandin levels) was thus sought. A mechanical method was eventually selected, application of a silver clip to the aortas of GH rats, just below the diaphragm, producing an immediate reduction in pressure distal to the constriction. Eighteen hours with later, PGI₂ production by these distal aortas those of matched sham GH controls and was was compared found to be consistently reduced. These results indicate that the ability to produce PGI₂ may be influenced by prior local pressure changes and that the increased capacity of hypertensive rat aortas to generate prostacyclin may be related to the increased mechanical transmural stress consequent on elevated pressure. Since haemostatic balance must be influenced not only by vascular PGI₂ generation but also by platelet sensitivity to PGI₂, the response of GH platelets to the anti-aggregatory effect of prostacyc1in was also investigated. As it had been shown by Sinzinger, Si1berbauer, Horsch and Gall (1981) that intra-arterial infusion of PGI₂ in humans decreased platelet sensitivity to the substance, the possibility existed that platelet sensitivity in hypertension might be reduced. This hypothesis was, however, invalidated as the sensitivity of GH platelets to the anti-aggregatory effect of PGI₂ was almost identical to that of normotensive controls. The shortcomings of the methodology and the possible importance of these findings in the hypertensive animal are discussed. The idea that elevated PGI₂ in hypertension may play a protective role both with respect to platelet aggregation and in attenuating further pressure rises is considered. It is finally suggested that it will be possible to draw more accurate conclusions as to the meaning of the increased PGI₂ generation in hypertension (both in relation to vascular tone and platelet function) only when details of production of, and sensitivity to, thromboxane A₂ are known. Thromboxane A₂ (TXA₂) is a vasoconstrictor and promotor of aggregation (Hamberg, Svensson and Samuelson, 1975) and it may be that, despite elevated vascular PGI₂ generation, the TXA₂/PGI₂ balance is still tipped in favour of vasoconstriction and platelet aggregation in hypertension.

Scanning and transmission electron microscopy and platelet aggregometry were employed to study erythrocyte morphology and thrombocyte morphology and function during ovine pregnancy-induced hypertension (OPIH). Nine multiparous gravid ewes were observed during normal pregnancy, OPIH, and thromboxane synthetase inhibitor administration. Blood pressure, plasma thromboxane B2, serum chemistries and electrolytes, fibrin/fibrinogen degratory products, and total platelet count were monitored throughout the investigation to document the circulatory environment during this syndrome. Arterial blood pressure, plasma thromboxane B2 levels, and serum chemistries and electrolytes were significantly altered (p≤0.005) during hypertension. However, no change in total platelet count or fibrin/fibrinogen degratory product levels were detected. Collagen-induced platelet aggregation also became abnormal during this time, while ADP-induced aggregatory response remained essentially unchanged. Platelet aggregation changes seemed to correspond to degranulation and swelling of the canalicular tubule system of these cells. Echinocytosis was present during baseline measurement and persisted throughout hypertension. However, changes in shistocyte numbers were not detected. Administration of the thromboxane synthetase inhibitors CGSl3080 or CGS12970 lowered blood pressure (p≤0.005) and serum thromboxane B₂ (p≤0.005), and. normalized serum chemistries and electrolytes (p≤0.005). Echinocyte numbers decreased (p≤0.05) and discocyte numbers increased (p≤0.005) after treatment. Platelet counts decreased after drug therapy, but normal collagen-induced aggregation was restored. No ultrastructural abnormalities were observed in thrombocytes after treatment. There is good evidence that thromboxane synthetase inhibition is appropriate and effective treatment for pregnancy-induced hypertension. These data suggest that such therapy is especially indicated in cases complicated by hematologic disorders as evidenced in an ovine model of this syndrome. / Master of Science

Liu, Yi. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 154-175). / Abstracts also in Chinese. / Title from PDF title page (viewed on 25, October, 2016).

Abstract Primary intracerebral hemorrhage (ICH) comprises 10–15% of all strokes. Arterial hypertension and warfarin use are well documented risk factors for ICH, but aspirin use also seems to predispose to ICH. The annual incidence of primary ICH in western populations is 12–31 / 100,000. Mortality is high: 14–52% during the first month and 14–80% during the first year after ICH. The size and location of the hemorrhage, a midline shift in head computed tomography, intraventricular spread of the hemorrhage, level of consciousness on admission, and high blood glucose independently predict mortality. For a risk factor study, 98 consecutive patients admitted into the Department of Neurology, Oulu University Hospital, because of ICH between January 1993 and September 1995 were compared with 206 control subjects drawn from a population register. Thromboxane and prostacyclin biosynthesis were measured from serial urine samples of 43 patients. For outcome studies, all subjects (n = 208) with incident ICH during the study period in the population of Northern Ostrobothnia, Finland, were identified. Untreated hypertension was the main modifiable risk factor for ICH. Use of aspirin appeared to be a significant risk factor for ICH in the subjects with a history of epistaxis. Enhanced thromboxane and prostacyclin biosynthesis were observed in the acute phase and 3 months after ICH. Regular use of aspirin preceding ICH doubled the 3-month mortality rate compared with nonusers of aspirin/warfarin. Aspirin use also associated with early hematoma growth. Patients with ICH showed increased long-term mortality up to 7 years after ICH compared to controls. No excess mortality was observed among those with good recovery at 3 months, but those who were severely disabled at 3 months after ICH showed marked excess mortality.

Ho, Kwok Wa. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 60-65). / Abstracts in English and Chinese. / Chapter Chapter I / Chapter 1.1. --- Thromboxane A2 (TP) Receptors --- p.1 / Chapter 1.1.1. --- Gene structure of human TP receptors --- p.1 / Chapter 1.1.2. --- Isoforms of TP receptor --- p.1 / Chapter 1.1.3. --- Distribution and expression of TP receptors in human --- p.2 / Chapter 1.1.4. --- Signal transduction of TP receptors --- p.4 / Chapter 1.1.5. --- Major agonists of TP receptor in animals and humans --- p.7 / Chapter 1.1.5.1. --- Thromboxane A2 --- p.7 / Chapter 1.1.5.2. --- Prostaglandin H2 --- p.7 / Chapter 1.1.6. --- Functional studies: effect of TP receptor activation and blockade on vascular tone and atherosclerosis --- p.8 / Chapter 1.1.6.1. --- Effect of TP receptor activation --- p.8 / Chapter 1.1.6.1.1. --- On vaso-contraction --- p.8 / Chapter 1.1.6.1.2. --- On vaso-relaxation --- p.9 / Chapter 1.1.6.2. --- Effect of TP receptor blockade --- p.9 / Chapter 1.1.6.2.1. --- On endothelium dependent vaso-contraction --- p.9 / Chapter 1.1.6.2.2. --- On animal models related to atherosclerosis --- p.10 / Chapter 1.1.7. --- Objectives of current study --- p.10 / Chapter 1.2. --- Periadventitial Adipose (Fat) Tissue --- p.12 / Chapter 1.2.1. --- "General function, distribution and classification of fat" --- p.12 / Chapter 1.2.2. --- Representative endocrine/paracrine role of adipose tissues --- p.13 / Chapter 1.2.2.1. --- Leptin --- p.13 / Chapter 1.2.2.2. --- Angiotensinogen --- p.14 / Chapter 1.2.3. --- Functional studies on vessels with periadventital fat attached -The beginning of the story of adipcyte-derived relaxing factor (ADRF) --- p.15 / Chapter 1.2.3. --- Mechanisms behind the action of ADRF --- p.17 / Chapter 1.2.3.1. --- Nature of ADRF --- p.17 / Chapter 1.2.3.2. --- The mechanisms controlling the release of ADRF --- p.17 / Chapter 1.2.3.3. --- Proposed mechanisms explaining the anti-contractile effect mediated by ADRF --- p.17 / Chapter 1.2.4. --- Objectives of current study --- p.20 / Chapter Chapter II / Chapter 2.1. --- Tissue Preparation --- p.21 / Chapter 2.1.1. --- Preparation of blood vessels --- p.21 / Chapter 2.1.2. --- Procedures to remove the endothelium --- p.21 / Chapter 2.2. --- The Organ Bath Setups --- p.22 / Chapter 2.3. --- Calculation of Results --- p.24 / Chapter 2.3.1. --- Calculation of active tension --- p.24 / Chapter 2.3.2. --- Measurement of dry weight of arterial rings --- p.24 / Chapter 2.3.3. --- Measurement of the weight for periadventitial fat --- p.24 / Chapter 2.3.4. --- Statistic analysis --- p.24 / Chapter 2.4. --- Chemicals and Solutions --- p.25 / Chapter 2.4.1. --- Chemicals --- p.25 / Chapter 2.4.2. --- Solutions --- p.26 / Chapter Chapter III --- Stimulation of TP receptors by U46619 inhibits cGMP dependent vaso-relaxation --- p.27 / Chapter 3.1. --- Detail methods and materials --- p.27 / Chapter 3.1.1. --- "Safety announcement, tissue preparation and materials" --- p.27 / Chapter 3.1.1. --- Protocol --- p.27 / Chapter 3.1.1.1. --- PartI --- p.27 / Chapter 3.1.1.2. --- Part II --- p.28 / Chapter 3.1.1.3. --- Part III --- p.28 / Chapter 3.2. --- Results --- p.29 / Chapter 3.2.1. --- Effect of U46619 on vaso-relaxation --- p.29 / Chapter 3.2.2. --- Effect of Rho kinase and phosphodiesterase inhibitor on the inhibitory effect of U46619 --- p.29 / Chapter 3.2.3. --- The effect of low concentration of U46619 on vaso-relaxation --- p.29 / Chapter 3.3. --- Discussion --- p.37 / Chapter 3.3.1. --- Implication of the current study --- p.37 / Chapter 3.3.2. --- Formulated Theory --- p.41 / Chapter Chapter IV --- Effect of periadventitial fat on anti-relaxation effect induced by U46619 - A preliminary test --- p.43 / Chapter 4.1. --- Detail methods and materials --- p.43 / Chapter 4.1.1. --- "Safety announcement, tissue preparation and materials" --- p.43 / Chapter 4.1.2. --- Protocol --- p.43 / Chapter 4.1.2.1. --- Part I --- p.43 / Chapter 4.1.2.2. --- Part II --- p.44 / Chapter 4.1.2.3. --- Part III --- p.44 / Chapter 4.1.2.4. --- Part IV --- p.44 / Chapter 4.2. --- Results --- p.45 / Chapter 4.2.1. --- Effect of periadventitial fat on vaso-relaxation of rings contracted by phenylephrine --- p.45 / Chapter 4.2.2. --- Effect of periadventitial fat on vaso-relaxation of rings contracted by U46619 plus phenylephrine --- p.45 / Chapter 4.2.3. --- Effect of S18886 on vaso-relaxation in endothelium removed rings --- p.45 / Chapter 4.2.4. --- Effect of elevated extracellular potassium ions on vaso-relaxation --- p.46 / Chapter 4.3. --- Discussion --- p.56 / Chapter 4.3.1. --- Implication of current study --- p.56 / Chapter 4.3.2. --- Improvements and future perspectives of current study --- p.58 / Summary --- p.59 / References --- p.60

Further studies were done to investigate the mechanism responsible for 1-BI-induced apoptosis in NCI-H460. It was found that 1-BI stimulated the expression of pro-apoptotic p53, Bax and cytosolic NF-kB p65 subunit but decreased pERK in NCI-H460 cells. The active forms of caspase 3 and caspase 9 were detected by Western blot, accompanied by an increase in caspase 3 activity. Reactive oxygen species (ROS) was highly generated at 24 hours after the treatment and the mitochondrial membrane potential was significantly decreased at 48 and 72 hours. The application of either N-acetyl cysteine (NAC) or glutathione (GSH) attenuated the cell growth inhibition caused by 1-BI. NCI-H460 cells pretreated with NAC showed a decrease in ROS production and p65 protein but an increase in pERK. / Taken together, these findings suggest that the inhibition of THXS suppresses lung cancer cell growth by promoting either G1 cell cycle arrest or apoptosis. The status of p53 is critical for both cell cycle arrest and apoptosis in 1-BI-mediated growth inhibition, which is evident by enhanced apoptosis detected in p53-transfected NCI-H23 and DMS 114 cells and G1 cell cycle in lung cancer cells treated with PFT-alpha. The 1-BI-induced growth-inhibitory pathway is associated with the generation of ROS, alteration of mitochondrial membrane potential, down-regulation of pERK and p65. / The result showed that THXS expressed in all of the three lung cancer cell lines (NCI-H23, DMS 114 and NCI-H460). The activity of THXS was also reflected by the presence of THXS metabolite thromobxane B2 (TXB2) in the cells, which was detected by ELISA. 1-Benzylimidazole (1-BI), a specific THXS inhibitor, suppressed the lung cancer cell proliferation measured by MTT assay. 1-BI treatment caused G1 phase arrest and enhanced the level of cyclin dependent kinase inhibitor p27 in a time-dependent manner in NCI-H23 and DMS 114 cells. It markedly increased DNA fragmentation in NCI-H460 cells. The findings suggest that 1-BI inhibits cell growth by arresting cell cycle and inducing cell death. Annexin V/PI staining revealed that the cell death induced by I-BI was mainly in the format of apoptosis. Further experiments showed that the I-BI-induced apoptosis could be enhanced by the introduction of p53 into NCI-H23 and DMS 114 cells, and such enhancement was associated with a decrease in mitochondrial membrane potential. This result suggests that the p53 may play a positive role in apoptosis induced by 1-BI through changing of the mitochondrial membrane potential. The role of p53 in I-BI-mediated apoptosis was further confirmed by the experiment of the p53 inhibition. Pifithrin-alpha hydrobromide (PFT-alpha), a p53 specific inhibitor, suppressed the 1-BI-induced p53 protein expression and increased G1 cell cycle arrest. / Thromboxane A2 (TXA2) is a potent arachidonate metabolite in the cyclooxygenase-2 (COX-2) pathway, which is produced by a member of cytochrome P450 (CYP) superfamily called thromboxane synthase (THXS). Recent studies have showed that thromboxane and THXS are associated with cancer cell migration, angiogenesis, tumor metastasis and cancer proliferation but there is limited information on their role in lung cancer development. This thesis is to test the hypothesis that inhibition of THXS could alter lung cancer cell growth. / Leung, Kin Chung. / Adviser: George G. Chen. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3319. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 130-144). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.