Abstract Adrenomedullin (AM) is a 52-amino acid peptide which is produced in many tissues, including adrenal medulla, lung, kidney and heart. Intravenous administration of AM causes a long-lasting hypotensive effect, accompanied with an increase in the cardiac output in experimental animals. This study was aimed to examine whether AM has any direct effects on myocardial function. In addition to the myocardial contractility, the effects of AM on coronary vascular tone and A-type natriuretic peptide (ANP) release from atria and B-type natriuretic peptide (BNP) gene expression in the ventricles were studied in the perfused rat heart preparation. In spontaneously beating hearts, AM had no effects on the heart rate, but dose-dependently increased the developed tension (DT) with an EC50 of 7 x 10-11 nmol/l, reflecting a potent positive inotropic effect. The lower the initial resting tension, the higher was the elevation in DT. In paced hearts, a protein kinase A inhibitor, H-89, had no effect on AM-induced inotropic effect, and AM did not increase the cAMP content of the ventricular myocardium. In contrast, the inhibitors of sarcoplasmic reticulum Ca2+ stores, ryanodine and thapsigargin, as well as a protein kinase C inhibitor, staurosporine, significantly attenuated the inotropic response to AM. L-type Ca2+ channel blocker, diltiazem, also suppressed the AM-induced elevation in DT. Moreover, AM increased the duration of myocyte action potentials between 10 mV and - 50 mV in isolated rat atria, consistent with an increase in L-type Ca2+ channel current during the plateau. Inotropic effect of endothelin-1 (ET-1), another locally acting peptide, was enhanced by inhibiting the myocardial nitric oxide (NO) synthesis by Nω-nitro-L-arginine methyl ester (L-NAME) in perfused rat heart. The AM-induced inotropic action was unaltered by L-NAME treatment. When AM and ET-1 were administrated in combined infusion, the inotropic response was significantly smaller than that following the infusion of the peptides alone. This attenuated response was more than overcome by infusion of L-NAME, although the individual responses to AM and ET-1 were not modulated by L-NAME at the doses used in the combination. Consistent with its vasodilator action, AM dose-dependently dilated the coronary arteries of the perfused heart. The effect of AM was not dependent on NO under basal conditions or in coronary arteries constricted with ET-1. Furthermore, AM enhanced the stretch-induced release of ANP from the right atrium, but did not affect the ventricular BNP expression induced by ET-1. In conclusion, AM exerts regulatory actions on the heart by increasing cardiac contractility, dilating coronary arteries and modulating stretch-induced ANP release. The inotropic effect of AM was independent of cyclic AMP, but may involve activation of protein kinase C, Ca2+ influx through L-type Ca2+ channels and the release of Ca2+ from the sarcoplasmic reticulum. Endogenous NO production did not modulate the inotropic effect of AM, although the effect of ET-1 was suppressed. Combined administration of AM and ET-1 produced a weak inotropic response most likely because of a potentiated synthesis of NO. Finally, AM had a coronary vasodilator effect and augmented the stretch-induced ANP release in the right atrium.

The incidence of restenosis has been shown to be correlated with the overstretching of the arterial wall during an angioplasty procedure. It has been proposed that slow balloon inflation results in lower intramural stresses, therefore minimizing vascular injury and restenosis rate. The analysis of the biomechanics of the arterial tissue might contribute to understand which factors trigger restenosis. However, few mechanical data are available on human arteries because of the difficulty of testing artery samples often obtained from autopsy while arteries are still considered "fresh". Various solutions mimicking the physiological environment have been used to preserve artery samples from harvesting to testing. In vitro mechanical testing is usually preferred since it is difficult to test arteries in vivo. Uniaxial and biaxial testing has been used to characterize anisotropic materials such as arteries, although methodological aspects are still debated. Several objectives were formulated and analyzed during the making of this thesis. In one study, the effect of deformation rate on the mechanical behavior of arterial tissue was investigated. The effect of several preservation methods, including cryopreservation, on the mechanical properties of porcine thoracic aortas was also analyzed. Finally, the differences in the mechanical behavior between three different types of sample geometry and boundary conditions were compared under uniaxial and equi-biaxial testing. Thoracic aortas were harvested within the day of death of pigs from a local slaughterhouse. Upon arrival, connective tissue was removed from the external wall of the artery. Then the artery was cut open along its length and cut out in rectangular samples for uniaxial testing, and square and cruciform samples for biaxial testing. Samples belonging to the freezing effect study were preserved for two months at -20°C and -80°C in isotonic saline solution, Krebs-Henseleit solution with 1.8 M dimethylsulfoxide, and dipped in liquid nitrogen. Samples belonging to the deformation rate effect study were tested uniaxially and equi-biaxially at deformation rates from 10 to 200 %/s. The uniaxial and biaxial experiments were simulated with the help of an inverse finite element software. The use of inverse modeling to fit the material properties by taking into account the non-uniform stress distribution was demonstrated. A rate-dependent isotropic hyperelastic constitutive equation, derived from the Mooney-Rivlin model, was fitted to the experimental results (i.e. deformation rate study). In the proposed model, one of the material parameters is a linear function of the deformation rate. Overall, inverse finite element simulations using the proposed constitutive relation accurately predict the mechanical properties of the arterial wall. In this thesis, it was found that easier attachment of samples (rectangular and cruciform) is accomplished using clamps rather than hooks. It was also found that the elastic behavior of arteries is nonlinear and non-isotropic when subjected to large deformations. Characterization of the arterial behavior at large deformations over a higherdeformation range was achieved using cruciform samples. The mechanical properties of arteries did not significantly change after preservation of arteries for two months. Under uniaxial and biaxial testing, loading forces were reduced up to 20% when the deformation rate was increased from 10 to 200 %/s, which is the opposite to the behaviour seen in other biological tissues. The differences observed in the mechanical behavior of fresh and thawed samples were not significant, independently of the storing medium or freezing temperature used. The lack of significant differences observed in the freezing study was likely due to the small number of samples tested per storing group. Further studies are required to clarify the impact of cryopreservation on extracellular matrix architecture to help tailor an optimized approach to preserve the mechanical properties of arteries. From the results obtained in the deformation rate study, it is concluded that the stiffness of arteries decreases with an increase in the deformation rate. In addition, the effect of deformation rate was observed to be higher than the effect of anisotropy. The inverse relationship between stiffness and deformation rate raises doubts on the hypothesized relationship between intramural stress, arterial injury, and restenosis. / Applied Science, Faculty of / Chemical and Biological Engineering, Department of / Graduate

Indiana University-Purdue University Indianapolis (IUPUI) / This research focuses on the detection of arterial blockage due to LDL (low density lipoprotein). Arterial blockages are related to two kinds of fats LDL and the HDL. HDL being the good fat, the patient does not have to undergo the biopsy, while in case of LDL, biopsy should be performed. Issues associated with invasive approaches raise safety concerns for patients such as infection, longer operation durations, longer recovery time etc. This research focuses on a noninvasive imaging technique to detect the kind of block age. Photo acoustic approach was investigated in order to simulate human tissues leading to medical diagnosis and treatment. Photo acoustic imaging involves production of an image on absorption of laser pulses. The laser pulses are further scattered and absorbed producing heat. The goals of the study were to categorize the type of the tissue materials based on the output temperature distribution via IR sensors and reflected acoustic waves via acoustic pressure sensors. The reflected acoustic wave and IR thermal distribution may be applied towards arterial blockages to differentiate the different types of tissue layers. The simulation results should have implications towards the future implementation of the practical devices and system. Parameters including energy levels, tissue thicknesses, frequencies, penetration depth, and the densities of the LDL/HDL fat materials were considered. Various energy pulses; 1j, 3j, and 5j were considered as input sources to the tissue materials (single or multi layers). The simulated layers considered in the study were the skin, bone, blood, and fat cells. The temperature and acoustic pressure response over the various layers were analyzed for the detection of blockages. The ndings of the temperature and acoustic pressure ranges can be detected by MEMS/NEMS (Micro electro mechanical systems/ nano electro mechanical systems) sensors, such as IR and Piezoelectric devices. Bioheat and acoustic wave equations were solved simultaneously using COMSOL software for multiple layers. The proper boundary conditions were provided in the solutions of these equations. The scattering and transmission acoustic wave, and the temperature distributions, may be used as guide to the integrated sensor system design for future consideration. The simulation was performed in four stages: (1) Single layer and multiple layers at a given frequency and energy level (2) Multiple layers at a given frequency for different energy levels (3) Multiple layers at a given energy level for different frequency and (4) Multiple layers at a given frequency and energy levels with different size tissues. The simulation results showed that a range of acoustic pressure between 240 and 260 need to be detected, with a di erential temperature distribution in kelvin range. Power pulses of 10MPa showed a temperature change of 175, which is believed to be within the exible substrate sensing devices that may be used for the practical model of this research. The thesis covers a proposed system for the practical model following the simulation results received in this study.

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Finally, the effects of external physical factors, such as temperature and contact force, on BP estimation based on m-NHA, were discussed and verified by experiments. Especially, a computational efficient algorithm was developed based on an optical model for motion resistant BP estimation, as well as the estimation of blood oxygen saturation (SaO2). We first developed an optical model with motion effect based on the photon-diffusion analysis, instead of the Beer-Lambert's law, which generally describes the light absorption but fails to account for light scattering in tissue. Based on the optical model, a novel motion resistant algorithm, minimum correlation discreet saturation transform (MCDST), was proposed for the estimation of arterial BP and SaO 2 as well. The novel algorithm is based on the time and time-delayed independence of the "true" signal and motion noise by use of dual PPGs (pulse oximeter). Experimental results indicate that MCDST has a comparable performance in SaO2 estimation and m-NHA calculation, as compared to another clinically verified motion-resistant algorithm---discreet saturation transform (DST). Most importantly, MCDST is much more computationally efficient than DST, because the former only uses simple linear algebra, while the latter uses the adaptive filter. It indicates that MCDST can reduce the required power consumption and circuit complexity of the implementation. It is vitally important for wearable devices, where the small physical size and long battery life are crucial. / First of all, a modified left-ventricle (LV) arterial coupling model was developed by incorporating a nonlinear pressure dependent compliance and two resistances for valve stenosis. A modified LV-arterial coupling model with pressure dependent compliance and taking into account the hypertensives with valve stenosis is quite necessary for proper description of the BP regulation for hypertensives with mitral and/or aortic stenosis, as well as normal people. / Hypertension is the most common cardiovascular disease and is a major public health problem in both developed and developing countries. As hypertension is often asymptomatic, continuous monitoring of blood pressure (BP) for the initiate treatment before the onset of organ damage is of vital importance for home healthcare. However, most of current BP meters, such as sphygmomanometer, are not suitable for the targeted applications because they provide only intermittent blood pressure readings and may cause circulatory interference with the usage of cuff. Moreover, they are not applicable in mobile environment due to the bulky design and the lack of efficient motion resistant algorithms. The objective of this research is to propose a motion resistant method for noninvasive and continuous BP measurement using dual photoplethysmograms (PPG), which could be potentially embedded in the portable or wearable devices for long term BP monitoring. / In summary, the research in this thesis not only covers the fundamental work, such as the modification of heart-arterial system coupling model and the proposal of a novel signal processing method MCDST, but also includes the practical techniques for the estimation of arterial BP as well as oxygen saturation. Expectations for further studies are suggested at the end of this thesis. / Secondly, based on the modified model, a novel parameter, normalized harmonic area (NHA), was proposed for BP estimation by quantifying the frequency distribution in the simulated aortic pressure waveforms. The excellent relationship between NHA and BP was verified by the simulation results. To establish a measurable parameter corresponding to NHA, PPG is investigated because it is widely used for the peripheral circulation monitoring and can be easily obtained at any location on the skin surface. Based on the assumption of quadratic transfer function from aortic pressure to PPG at fingertip, the discreet period transform (DPT) was applied on PPG signal to produce a modified NHA (m-NHA) for BP estimation. For the clinical tests on 85 subjects, the difference between the estimated and the measured blood pressure by m-NHA is 0.97+/-7.9mmHg for systolic blood pressure (SBP) and 0.40+/-4.5mmHg for diastolic blood pressure (DBP), respectively. This result is as good as that (0.73+/-7.6mmHg for SBP, and 0.40+/-4.5mmHg for DBP) from the widely reported pulse transit time (PTT) approach. / Yan Yongsheng. / "November 2005." / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6561. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references. / 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.

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

Object Rupture of intracranial arteriovenous malformations is a leading cause of stroke in children and young adults. Treatment options include surgery and highly focused radiation (stereotactic radiosurgery). For large and deep seated lesions, the risks of surgery may be prohibitively high, while radiosurgery has a disappointingly low efficacy and long latency. Radiosurgery carries the most promise for significant advances, however the process by which radiosurgery achieves obliteration is incompletely understood. Inflammation and thrombosis are likely to be important in the radiation response and may be amenable to pharmacological manipulation to improve radiosurgical efficacy. Materials and methods Immunohistochemistry and electron microscopy were used to study normal cerebral vessels, cavernous malformations and AVMs, some of which had previously been irradiated. An attempt was made to culture AVM endothelial cells to study the immediate response of AVM endothelium to radiosurgery. The effects of radiosurgery in a rat model of AVM were studied using immunohistochemistry and the results used to determine the choice of a pharmacological strategy to enhance the thrombotic effects of radiosurgery. Results Vascular malformations have a different endothelial inflammatory phenotype than normal cerebral vessels. Radiosurgery may cause long term changes in inflammatory molecule expression and leads to endothelial loss with exposure of pro-thrombotic molecules. Ultrastructural effects of irradiation include widespread cell loss, smooth muscle cell (SMC) proliferation and thrombosis. Endothelial culture from AVMs proved difficult due to SMC predominance in initial cultures. Radiosurgery upregulated several endothelial inflammatory molecules in the animal model and may induce pro-thrombotic cell membrane alterations. The administration of lipopolysaccharide and soluble tissue factor to rats following radiosurgery led to selective thrombosis of irradiated vessels. Conclusions Inflammation and thrombosis are important in the radiosurgical response of AVMs. Lumen obliteration appears to be mediated by proliferation of cells within the vessel wall and thrombosis. Upregulation of inflammatory molecules and perhaps disruption of the normal phospholipid asymmetry of the endothelial and SMC membranes are some of the earliest responses to radiosurgery. The alterations induced by radiation may be harnessed to selectively initiate thrombus formation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing treatable lesion size and reducing latency.