Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

published_or_final_version / abstract / Pharmacology / Doctoral / Doctor of Philosophy

Kai Hong Kwok. / Thesis submitted in: December 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 90-98). / Abstract also in Chinese. / Chapter Chapter 1 --- Introduction / Chapter 1.1. --- Classification of β-adrenoceptor in cardiovascular system --- p.1 / Chapter 1.2. --- Vasodilator effects of β-adrenoceptor-agonists and their mechanisms --- p.4 / Chapter 1.3. --- Role of endothelium in β-adrenoceptor-mediated vasodilation --- p.7 / Chapter 1.4. --- Role of K+ channels in β-adrenoceptor-mediated relaxation --- p.11 / Chapter 1.5. --- Other aspect regarding the vascular response to stimulation of B-adrenoceptor --- p.15 / Chapter 1.6. --- Clinical aspect of B-adrenoceptor agents --- p.15 / Chapter Chapter 2 --- Methods and Materials / Chapter 2.1. --- Tissue Preparation --- p.19 / Chapter 2.1.1. --- Preparation of the isolated rat mesenteric artery --- p.19 / Chapter 2.1.2. --- Removal of the functional endothelium --- p.19 / Chapter 2.1.3. --- Organ bath set-up --- p.20 / Chapter 2.1.4. --- Length-tension relationship and an optimal resting tension --- p.22 / Chapter 2.2. --- Experimental Procedure --- p.22 / Chapter 2.2.1. --- Relaxant effects of the B-adrenoceptor agonists --- p.24 / Chapter 2.2.2. --- Effects of putative K+ channel blockers --- p.24 / Chapter 2.2.3. --- Effects of inhibitors of nitric oxide activity --- p.25 / Chapter 2.2.4. --- Effect of indomethacin --- p.25 / Chapter 2.2.5. --- "Effects of K+ channel opener, nitric oxide donor and forskolin" --- p.26 / Chapter 2.3. --- Chemicals and Solutions --- p.26 / Chapter 2.3.1. --- Chemicals and drugs --- p.26 / Chapter 2.3.2. --- Preparation of drug stock solutions --- p.26 / Chapter 2.3.3. --- Solutions --- p.28 / Chapter 2.4. --- Statistical Analysis --- p.28 / Chapter Chapter 3 --- Results / Chapter 3.1. --- Relaxant Effect of Isoprenaline --- p.29 / Chapter 3.1.1. --- Relaxant effect of isoprenaline --- p.29 / Chapter 3.1.2. --- Effects of inhibitors of nitric oxide activity --- p.29 / Chapter 3.1.3. --- Effect of charybdotoxin on the vasorelaxant response to isoprenaline --- p.32 / Chapter 3.1.4. --- Effect of glibenclamide on the vasorelaxant response to isoprenaline --- p.32 / Chapter 3.1.5. --- Effect of TPA+ on isoprenaline-induced relaxation --- p.36 / Chapter 3.1.6. --- Effect of TPA+ in the presence of iberiotoxin or glibenclamide --- p.36 / Chapter 3.1.7. --- Effect of Ba2+ on the vasorelaxant effect of isoprenaline --- p.41 / Chapter 3.1.8. --- Effect of raising extracellular K+ on isoprenaline-mediated relaxation --- p.41 / Chapter 3.2. --- Relaxant Effect of Dobutamine --- p.44 / Chapter 3.2.1. --- Effects of inhibitors of endothelium-derived factors on the relaxant effect of dobutamine --- p.44 / Chapter 3.2.2. --- Antagonism of the effect of dobutamine by β1-adrenoceptor antagonist --- p.44 / Chapter 3.2.3. --- Effects of putative Kca channel blockers on the relaxant effect of dobutamine --- p.51 / Chapter 3.2.4. --- Effect of TPA+ on the relaxant effect of dobutamine --- p.55 / Chapter 3.2.5. --- Effect of raising extracellular K+ on the relaxant effect of dobutamine --- p.55 / Chapter 3.3. --- Relaxant Effect of Fenoterol --- p.57 / Chapter 3.3.1. --- Effect of inhibitors of nitric oxide activity on the relaxant effect of fenoterol --- p.57 / Chapter 3.3.2. --- Effect of charybdotoxin on the relaxant effect of fenoterol --- p.57 / Chapter 3.3.3. --- Effect of TPA+ on the relaxant effect of fenoterol --- p.64 / Chapter 3.3.4. --- Effect of glibenclamide on the relaxant effect of fenoterol --- p.64 / Chapter 3.3.5. --- Effect of raising extracellular K+ on fenoterol-mediated relaxation --- p.64 / Chapter 3.4. --- Effects of cAMP- and cGMP-elevating agents --- p.69 / Chapter 3.4.1. --- Effects of inhibitors of endothelium-derived factors on the relaxation induced by nitroprusside and forskolin --- p.69 / Chapter 3.4.2 --- Effect of charybdotoxin on relaxant effect of forskolin --- p.69 / Chapter 3.4.3 --- Effect of Ba2+ on the vasorelaxant effect of forskolin --- p.76 / Chapter 3.4.4 --- Effect of TPA+ on the relaxant effect of forskolin --- p.76 / Chapter 3.4.5 --- Effect of glibenclamide on the relaxant effects of forskolin and cromakalim --- p.76 / Chapter Chapter 4 --- Discussion / Chapter 4.1. --- Effect of Isoprenaline and Fenoterol --- p.77 / Chapter 4.2. --- Effect of Dobutamine --- p.83 / Chapter 4.3. --- Conclusion --- p.88 / References --- p.90 / Publications --- p.98

Typescript (photocopy) / v, 243 leaves, [4] leaves of plates : ill. ; 26 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.) Dept. of Physiology and Pharmacology, University of Adelaide, 1975

by Liu Kin Hung. / Thesis submitted in: Dec, 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 87-95). / Abstract also in Chinese. / Chapter 1 --- Introduction --- p.1 / Chapter 2 --- Literature Review --- p.3 / Chapter 2.1 --- Venous anatomy --- p.3 / Chapter 2.2 --- Arterial anatomy --- p.6 / Chapter 2.3 --- Deep vein thrombosis --- p.8 / Chapter 2.3.1 --- Clinical Examination --- p.11 / Chapter 2.3.2 --- Contrast Venogram --- p.12 / Chapter 2.3.3 --- Color duplex ultrasound --- p.13 / Chapter 2.4 --- Arterial resistance --- p.24 / Chapter 2.5 --- Basis for study --- p.28 / Chapter 3 --- Method --- p.30 / Chapter 3.1 --- Subjects --- p.30 / Chapter 3.2 --- Equipments --- p.30 / Chapter 3.3 --- Procedure --- p.31 / Chapter 3.4 --- Data analysis --- p.38 / Chapter 4 --- Results --- p.40 / Chapter 4.1 --- Arterial resistance changes in different groups --- p.40 / Chapter 4.1.1 --- Symptomatic with no DVT versus asymtomatic with no DVT --- p.40 / Chapter 4.1.2 --- Symptomatic with DVT versus symptomatic with no DVT --- p.43 / Chapter 4.1.3 --- Symptomatic acute DVT versus symptomatic chronic DVT --- p.46 / Chapter 4.1.4 --- Symptomatic proximal-DVT versus symptomatic calf-DVT --- p.49 / Chapter 4.1.5 --- symptomatic occlusive DVT versus symptomatic non- occlusive DVT --- p.52 / Chapter 4.2 --- Diagnosis of DVT by arterial resistance changes --- p.57 / Chapter 4.2.1 --- Detection of presence of symptomatic DVT --- p.57 / Chapter 4.2.2 --- Differentiation of characteristics of symptomatic DVT --- p.60 / Chapter 5 --- Discussion --- p.64 / Chapter 5.1 --- Investigation of arterial resistance changes --- p.64 / Chapter 5.1.1 --- Symptomatic with no DVT versus asymtomatic with no DVT --- p.66 / Chapter 5.1.2 --- Symptomatic with DVT versus symptomatic with no DVT --- p.69 / Chapter 5.1.3 --- Symptomatic acute DVT versus symptomatic chronic DVT --- p.72 / Chapter 5.1.4 --- Symptomatic proximal-DVT versus symptomatic calf-DVT --- p.74 / Chapter 5.1.5 --- symptomatic occlusive DVT versus symptomatic non- occlusive DVT --- p.76 / Chapter 5.2 --- Detection and differentiation of DVT by arterial resistance --- p.80 / Chapter 5.2.1 --- Detection of symptomatic DVT --- p.80 / Chapter 5.2.2 --- Differentiation of occlusive DVT from non-occlusive DVT --- p.82 / Chapter 6 --- Conclusion --- p.85 / Chapter 7 --- References --- p.87

Chan Hoi Yun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 131-144). / Abstracts in English and Chinese. / DECLARATION --- p.i / ACKNOWLEDGMENTS --- p.ii / ABBREVIATIONS --- p.iii / ABSTRACT IN ENGLISH --- p.v / ABSTRACT IN CHINESE --- p.viii / CONTENTS --- p.xi / Chapter Chapter 1 --- Introduction / Chapter 1.1. --- Steroid Hormones --- p.1 / Chapter 1.1.1. --- Synthesis of estrogens and progesterone --- p.1 / Chapter 1.2. --- Cellular Mechanisms of Female Steroid Hormones --- p.5 / Chapter 1.2.1. --- Genomic actions of female steroid hormones --- p.5 / Chapter 1.2.2. --- Non-genomic actions of female steroid hormones --- p.7 / Chapter 1.2.3. --- Estrogen antagonists --- p.7 / Chapter 1.2.3.1. --- Classification of estrogen antagonists --- p.7 / Chapter 1.2.3.2. --- Mechanisms of estrogen antagonists --- p.9 / Chapter 1.3. --- Chronic (genomic) Effects of 17β-Estradiol and Progesterone --- p.10 / Chapter 1.3.1. --- Effects of lipid metabolism --- p.10 / Chapter 1.3.2. --- Effects on cell proliferation --- p.11 / Chapter 1.3.3. --- Effects on endothelial cells --- p.12 / Chapter 1.4. --- Acute Effects of 17β-Estradiol and Progesterone --- p.13 / Chapter 1.4.1. --- Role of endothelium in 17β-estradiol or progesterone Relaxation --- p.13 / Chapter 1.4.2. --- Involvement of plasma membrane estrogen receptors --- p.14 / Chapter 1.4.3. --- Role of Ca2+ and K+ channel in estrogen relaxation --- p.14 / Chapter 1.4.4. --- Interaction with vasoconstrictors --- p.15 / Chapter 1.4.5. --- Interaction with endothelium-dependent dilators --- p.16 / Chapter 1.4.6. --- Interaction with adrenergic response --- p.17 / Chapter 1.5. --- Clinical Studies --- p.19 / Chapter 1.6. --- Therapeutic Values of Estrogen and Progesterone --- p.20 / Chapter 1.7. --- Objectives of the Present Study --- p.22 / Chapter Chapter 2 --- Method and Materials / Chapter 2.1. --- Tissue Preparation --- p.25 / Chapter 2.1.1. --- "Preparation of the rat aorta, mesenteric artery and carotid Artery" --- p.25 / Chapter 2.1.2. --- Removal of the functional endothelium --- p.26 / Chapter 2.2. --- Organ Bath Set-up --- p.26 / Chapter 2.3. --- Force Measurement --- p.28 / Chapter 2.3.1. --- Vascular action of 17β-estradiol and progesterone --- p.29 / Chapter 2.3.1.1. --- Role of endothelium/nitric oxide in 17β-estradiol- or progesterone-induced relaxation --- p.29 / Chapter 2.3.1.2. --- Role of inducible nitric oxide in progesterone-induced relaxation --- p.30 / Chapter 2.3.1.3. --- Effect of estrogen receptor inhibitor on 17β-estradiol- induced relaxation --- p.30 / Chapter 2.3.1.4. --- Interaction between progesterone and 17β-estradiol --- p.31 / Chapter 2.3.1.5. --- Effect of 17β-estradiol on protein kinase C-mediated contraction --- p.31 / Chapter 2.3.1.6. --- Synergistic interaction between β-adrenoceptor agonists and 17β-estradiol --- p.32 / Chapter 2.4. --- Porcine Coronary Artery Experiments --- p.33 / Chapter 2.4.1. --- Vessel preparation --- p.33 / Chapter 2.4.2. --- Force measurement --- p.33 / Chapter 2.4.3. --- Experimental protocol --- p.34 / Chapter 2.4.3.1. --- Effect of physiological level of 17β-estradiol on β- adrenoceptor agonist-induced relaxation --- p.34 / Chapter 2.4.3.2. --- Effect of physiological level of 17β-estradiol on phosphodiesterase inhibitor-induced relaxation --- p.34 / Chapter 2.5. --- Ovariectomy --- p.35 / Chapter 2.5.1. --- Method of ovariectomy --- p.35 / Chapter 2.5.2. --- Preparation of blood vessels --- p.36 / Chapter 2.5.3. --- Experimental protocols --- p.38 / Chapter 2.5.3.1. --- Effect of ovariectomy on contractility of rat carotid arteries --- p.38 / Chapter 2.5.3.2. --- Effect of ovariectomy on relaxation of rat carotid arteries --- p.38 / Chapter 2.6. --- Chemicals and Solutions --- p.39 / Chapter 2.7. --- Statistical Analysis --- p.42 / Chapter Chapter 3 --- Results / Chapter 3.1. --- Role of Endothelium/Nitric Oxide in 17β-Estradiol- and Progesterone-induced Relaxations --- p.43 / Chapter 3.1.1. --- Relaxant response of 17β-estradiol --- p.43 / Chapter 3.1.2. --- Effects of inhibitors of nitric oxide activity on 17β- estradiol-induced relaxation --- p.46 / Chapter 3.1.3. --- Relaxant response of progesterone --- p.46 / Chapter 3.1.4. --- Effects of inhibitors of nitric oxide activity on progesterone-induced relaxation --- p.50 / Chapter 3.2. --- Effect of Estrogen Receptor Inhibitor on 17β-Estradiol- induced Relaxation --- p.56 / Chapter 3.3. --- Interaction between Progesterone and 17β-Estradiol --- p.56 / Chapter 3.4. --- Effect of Female Sex Steroid Hormones on Protein Kinase C-mediated Contraction --- p.59 / Chapter 3.4.1. --- Effect of 17β-estradiol on phorbol ester-induced contraction --- p.59 / Chapter 3.4.2. --- Effect of progesterone on phorbol ester-induced contraction --- p.59 / Chapter 3.5. --- Effects of β-adrenoceptor Agonists on 17β-Estradiol- induced Relaxations --- p.62 / Chapter 3.5.1. --- Effect of isoproterenol on 17β-estradiol-induced relaxation --- p.62 / Chapter 3.5.2. --- Role of endothelium/nitric oxide on the isoproterenol potentiation of 17β-estradiol-induced relaxation --- p.63 / Chapter 3.5.3. --- Role of cyclic AMP on isoproterenol-enhancement of 17β- estradiol-induced relaxation --- p.69 / Chapter 3.5.4. --- Effects of β-adrenoceptor antagonists --- p.69 / Chapter 3.6. --- Effects of Physiological Concentration of 17β-EstradioI onβ-adrenoceptor Agonists-induced Relaxationsin Porcine Coronary Artery --- p.77 / Chapter 3.6.1. --- Effect of 17β-estradiol on isoproterenol-induced relaxations --- p.77 / Chapter 3.6.2. --- Effect of 17β-estradiol on fenoterol-induced relaxations --- p.11 / Chapter 3.6.3. --- Effect of 17β-estradiol on dobutamine-induced relaxations --- p.81 / Chapter 3.6.4. --- Effect of 17β-estradiol on IBMX-induced relaxation --- p.86 / Chapter 3.7. --- Effect of Ovariectomy on the Vascualr Reactivity --- p.88 / Chapter 3.7.1. --- Effect of ovariectomy on the contractile activity of rat carotid artery --- p.88 / Chapter 3.7.1.1. --- Effect of ovariectomy on phenylephrine-induced contraction --- p.88 / Chapter 3.7.1.2. --- Effect of ovariectomy on U46619-induced contraction --- p.96 / Chapter 3.7.1.3. --- Effect of ovariectomy on high K+- induced contraction --- p.102 / Chapter 3.7.1.4. --- Effect of ovariectomy on acetylcholine-induced relaxation --- p.106 / Chapter Chapter 4 --- Discussions / Chapter 4.1. --- Role of Endothelium/Nitric oxide in 17β-Estradiol- and Progesterone-induced Relaxations --- p.110 / Chapter 4.2. --- Effect of Estrogen Receptor Inhibitor on 17β-Estradiol- induced Relaxation --- p.113 / Chapter 4.3. --- Interaction between Progesterone and 17β-Estradiol --- p.114 / Chapter 4.4. --- Effects of Female Sex Steroid Hormones on Protein Kinase C-mediated Contraction --- p.115 / Chapter 4.5. --- Effects of β-Adrenoceptor Agonists on 17β-Estradiol- induced Relaxations --- p.116 / Chapter 4.6. --- Effects of 17β-Estradiol on β-Adrenoceptor Agonists- induced Relaxations in Porcine Coronary Artery --- p.121 / Chapter 4.7. --- Effect of Ovariectomy on the Vascular Reactivity --- p.125 / Chapter 4.8. --- Conclusions --- p.129 / References --- p.131 / Publications --- p.145

Statins induce beneficial vascular effects. How statins induce beneficial vascular effects is yet to be determined. Here we examine Simvastatin and vascular endothelial growth factor (VEGF) acting through the phosphoinositide 3-kinase (PI3K) pathway in human coronary artery endothelial cells (HCAEC). While Simvastatin and VEGF both activated mediators in the PI3K pathway, the proteins and the rates of activation were not always consistent. This suggests that although Simvastatin and VEGF share a common PI3K pathway in HCAEC and similar vascular effects, the agonists diverge in the induction of cellular signaling cascades. Simvastatin also was shown to induce phosphoinositide 3, 4, 5-triphosphate (PIPS) organization and PI3K p110 gamma (y) perinuclear localization. Beneficial, non-lipid lowering effects of statins may occur through the PI3K pathway through activation of distinct mediators from those of VEGF. Better understanding of the pathways associated with statins is necessary for the discovery of better treatments for cardiovascular disease (CVD). / Department of Biology

The mechanical behavior of the arterial wall is determined by the composition and structure of its internal constituents as well as the applied traction-forces, such as pressure and axial stretch. The purpose of this work is to develop new theoretical frameworks and experimental methodologies to further the understanding of arterial mechanics and role of the various intrinsic and extrinsic mechanically motivating factors. Specifically, residual deformation, matrix organization, and perivascular support are investigated in the context of their effects on the overall and local mechanical behavior of the artery. We propose new kinematic frameworks to determine the displacement field due to residual deformations previously unknown, which include longitudinal and shearing residual deformations. This allows for improved predictions of the local, intramural stresses of the artery. We found distinct microstructural differences between the femoral and carotid arteries from non-human primates. These arteries are functionally and mechanically different, but are geometrically and compositionally similar, thereby suggesting differences in their microstructural alignments, particularly of their collagen fibers. Finally, we quantified the mechanical constraint of perivascular support on the coronary artery by mechanically testing the artery in-situ before and after surgical exposure.

Indiana University-Purdue University Indianapolis (IUPUI) / Atherosclerotic lesions of human beings are common diagnosed in regions of arte- rial branching and curvature. The prevalence of atherosclerosis is usually associated with hardening and ballooning of aortic wall surfaces because of narrowing of flow path by the deposition of fatty materials, platelets and influx of plasma through in- timal wall of Aorta. High Wall Shear Stress (WSS) is proved to be the main cause behind all these aortic diseases by physicians and researchers. Due to the fact that the atherosclerotic regions are associated with complex blood flow patterns, it has believed that hemodynamics and fluid-structure interaction play important roles in regulating atherogenesis. As one of the most complex flow situations found in cardio- vascular system due to the strong curvature effects, irregular geometry, tapering and branching, and twisting, theoretical prediction and in vivo quantitative experimental data regarding to the complex blood flow dynamics are substantial paucity. In recent years, computational fluid dynamics (CFD) has emerged as a popular research tool to study the characteristics of aortic flow and aim to enhance the understanding of the underlying physics behind arteriosclerosis. In this research, we study the hemo- dynamics and flow-vessel interaction in patient specific normal (healthy) and dilated (diseased) aortas using Ansys-Fluent and Ansys-Workbench. The computation con- sists of three parts: segmentation of arterial geometry for the CFD simulation from computed tomography (CT) scanning data using MIMICS; finite volume simulation of hemodynamics of steady and pulsatile flow using Ansys-Fluent; an attempt to perform the Fluid Structure Simulation of the normal aorta using Ansys-Workbench. Instead of neglecting the branching or smoothing out the wall for simplification as a lot of similar computation in literature, we use the exact aortic geometry. Segmen- tation from real time CT images from two patients, one young and another old to represent healthy and diseased aorta respectively, is on MIMICS. The MIMICS seg- mentation operation includes: first cropping the required part of aorta from CT dicom data of the whole chest, masking of the aorta from coronal, axial and saggital views of the same to extract the exact 3D geometry of the aorta. Next step was to perform surface improvement using MIMICS 3-matic module to repair for holes, noise shells and overlapping triangles to create a good quality surface of the geometry. A hexahe- dral volume mesh was created in T-Grid. Since T-grid cannot recognize the geometry format created by MIMICS 3-matic; the required step geometry file was created in Pro-Engineer. After the meshing operation is performed, the mesh is exported to Ansys Fluent to perform the required fluid simulation imposing adequate boundary conditions accordingly. Two types of study are performed for hemodynamics. First is a steady flow driven by specified parabolic velocity at inlet. We captured the flow feature such as skewness of velocity around the aortic arch regions and vortices pairs, which are in good agreement with open data in literature. Second is a pulsatile flow. Two pulsatile velocity profiles are imposed at the inlet of healthy and diseased aorta respectively. The pulsatile analysis was accomplished for peak systolic, mid systolic and diastolic phase of the entire cardiac cycle. During peak systole and mid-systole, high WSS was found at the aortic branch roots and arch regions and diastole resulted in flow reversals and low WSS values due to small aortic inflow. In brief, areas of sudden geometry change, i.e. the branch roots and irregular surfaces of the geom- etry experience more WSS. Also it was found that dilated aorta has more sporadic nature of WSS in different regions than normal aorta which displays a more uniform WSS distribution all over the aorta surface. Fluid-Structure Interaction simulation is performed on Ansys-WorkBench through the coupling of fluid dynamics and solid mechanics. Focus is on the maximum displacement and equivalent stress to find out the future failure regions for the peak velocity of the cardiac cycle.