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Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / In groups of African ancestry, who have a high prevalence of “salt-sensitive, low-renin” hypertension, there is considerable uncertainty as to relevance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of primary hypertension. In the present thesis I explored the possibility that the RAAS, through interactions with environmental effects, contributes to blood pressure (BP) in this ethnic group. After excluding participants with aldosterone-to-renin ratios (ARR) above the threshold for primary aldosteronism, in 575 participants of African ancestry, I demonstrated that with adjustments for confounders, an interaction between ARR and urinary Na+/K+ (and index of salt intake obtained from 24-hour urine samples) was independently associated with BP (p<0.0001). This effect was accounted for by interactions between serum aldosterone concentrations and urinary Na+/K+ (p<0.0001), but not between plasma renin concentrations and urinary Na+/K+ (p=0.52). The interaction between ARR and urinary Na+/K+ translated into a marked difference in the relationship between urinary Na+/K+ and BP in participants above and below the median for ARR (p<0.0001 for a comparison of the relationships). Having demonstrated that circulating aldosterone concentrations may account for a substantial proportion of the relationship between salt intake and BP in this community sample, I subsequently assessed whether genetic factors contribute toward serum aldosterone concentrations. In 153 randomly selected nuclear families of African ancestry consisting of 448 participants without primary aldosteronism, with, but not without adjustments for plasma renin concentrations, independent correlations were noted for iii serum aldosterone concentrations between parents and children (p<0.05), with parent-child partial correlation coefficients being greater than those for father-mother relationships (p<0.05). Furthermore, after, but not before adjustments for plasma renin concentrations, serum aldosterone concentrations showed significant heritability (h2=0.25±0.12, p<0.02). No independent relationships between RAAS gene polymorphisms and serum aldosterone concentrations were observed. I also aimed to assess whether RAAS genes modify the relationship between cigarette smoking and BP in groups of African descent. However, as the impact of mild smoking on BP is uncertain, and in the community studied only 14.5% smoked and the majority of smokers were mild smokers (mean=7.4±4.6 cigarettes per day) in 689 randomly participants I initially assessed the relationship between smoking habits and out-of-office BP. In this regard, current smokers had higher unadjusted and multivariate adjusted 24-hour systolic/diastolic BP (SBP/DBP in mm Hg) (p<0.005-p<0.0005) than non-smokers, effects that were replicated in sex-specific groups, non-drinkers, and in the overweight and obese. Current smoking was second only to age and at least equivalent to body mass index in the quantitative impact on out-of-office BP and the risk of uncontrolled out-of-office BP was increased in smokers as compared to non-smokers. Thus, despite minimal effects on in-office BP, predominantly mild current smoking was independently associated with an appreciable proportion of out-of-office BP in a community of African ancestry. In 652 participants I subsequently assessed whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism accounts for the strong relationships between predominantly mild smoking and out-of-office BP. After iv appropriate adjustments, an interaction between ACE DD genotype and current cigarette smoking, or the number of cigarettes smoked per day was independently associated with 24-hour and day diastolic BP (DBP) (p<0.05-0.005). This effect translated into a relationship between smoking and out-of-office BP or the risk for uncontrolled out-of-office BP only in participants with the DD as compared to the ID + II genotypes. In conclusion therefore, I afford evidence to suggest that in groups of African ancestry, aldosterone, within ranges that cannot be accounted for by the presence of primary aldosteronism, modifies the relationship between salt intake and BP, and that genetic factors account for the variation in serum aldosterone concentrations in this group. Furthermore, I show that the ACE gene modifies the relationship between smoking and out-of-office BP and hence accounts for even predominantly mild smoking producing a marked and clinically important effect on out-of-office BP. The present thesis therefore provides further evidence in favour of an important pathophysiological role for the RAAS in contributing toward BP in groups of African ancestry.

Tsang, Siu Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 107-121). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iii / Acknowledgements --- p.v / Table of Contents --- p.vi / List of Abbreviations --- p.x / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Renin-angiotensin system (RAS) --- p.1 / Chapter 1.1.1 --- Circulating RAS --- p.2 / Chapter 1.1.2 --- Tissue-specific RAS --- p.5 / Chapter 1.2 --- RAS inhibitors --- p.7 / Chapter 1.2.1 --- Angiotensin converting enzyme inhibitor --- p.8 / Chapter 1.2.2 --- Non-specific angiotensin II receptor blocker --- p.9 / Chapter 1.2.3 --- Specific AT1 receptor antagonist --- p.10 / Chapter 1.2.4 --- Specific AT2 receptor antagonist --- p.11 / Chapter 1.3 --- Pancreas and functions of exocrine pancreas --- p.14 / Chapter 1.3.1 --- Structure of pancreas --- p.14 / Chapter 1.3.2 --- Exocrine secretions and pancreatic enzymes --- p.16 / Chapter 1.3.3 --- Regulation of exocrine secretions --- p.17 / Chapter 1.4 --- Pancreatic RAS --- p.18 / Chapter 1.4.1 --- Expression and localization --- p.18 / Chapter 1.4.2 --- Regulation --- p.19 / Chapter 1.4.3 --- Clinical relevance to the pancreas --- p.20 / Chapter 1.5 --- Acute pancreatitis --- p.21 / Chapter 1.5.1 --- Pathogenesis --- p.21 / Chapter 1.5.2 --- Experimental models of acute pancreatitis --- p.22 / Chapter 1.5.3 --- Criteria of acute pancreatitis --- p.23 / Chapter 1.5.4 --- Oxidative stress in acute pancreatitis --- p.24 / Chapter 1.6 --- RAS and acute pancreatitis in exocrine pancreas --- p.26 / Chapter 1.6.1 --- RAS and acute pancreatitis --- p.26 / Chapter 1.6.2 --- RAS and pancreatic microcirculation --- p.26 / Chapter 1.6.3 --- RAS and tissue injury --- p.27 / Chapter 1.6.4 --- Exocrine pancreatic RAS and acute pancreatitis-induced injury --- p.28 / Chapter 1.7 --- Aims of study --- p.29 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Animal models and RAS inhibitors --- p.30 / Chapter 2.1.1 --- Cerulein-induced acute pancreatitis --- p.30 / Chapter 2.1.2 --- Prophylactic treatment with RAS inhibitors --- p.31 / Chapter 2.1.3 --- Therapeutic treatment with RAS inhibitors --- p.32 / Chapter 2.2 --- Evaluation of pancreatic injury --- p.32 / Chapter 2.2.1 --- Assessment of pancreatic water content --- p.33 / Chapter 2.2.2 --- Measurement of α-amylase activity in plasma --- p.33 / Chapter 2.2.3 --- Measurement of lipase activity in plasma --- p.34 / Chapter 2.3 --- Histopathological examinations --- p.34 / Chapter 2.3.1 --- Preparation of paraffin blocks --- p.35 / Chapter 2.3.2 --- Hematoxylin and eosin staining --- p.35 / Chapter 2.4 --- Biochemical assay of pancreatic oxidative status --- p.37 / Chapter 2.4.1 --- Sample preparation --- p.37 / Chapter 2.4.2 --- Quantification of protein content --- p.37 / Chapter 2.4.3 --- Measurement of glutathione levels --- p.38 / Chapter 2.4.4 --- Assessment of protein oxidation --- p.38 / Chapter 2.4.5 --- Assessment of lipid peroxidation --- p.39 / Chapter 2.4.6 --- Measurement of NADPH oxidase activity --- p.40 / Chapter 2.5 --- Studies of pancreatic digestive enzyme secretions from isolated acini --- p.40 / Chapter 2.5.1 --- Dissociation of acini from pancreatic tissue --- p.40 / Chapter 2.5.2 --- Treatment with peptides and RAS inhibitors --- p.42 / Chapter 2.5.3 --- Quantification of protein and DNA contents --- p.43 / Chapter 2.5.4 --- Measurement of a-amylase and lipase secretions --- p.44 / Chapter 2.5.5 --- RT-PCR analysis of RAS components in acinar cells --- p.44 / Chapter 2.6 --- Studies of RAS inhibitors on acute pancreatitis-induced systemic inflammation --- p.45 / Chapter 2.6.1 --- Systemic inflammation treatment --- p.45 / Chapter 2.6.2 --- Measurement of myeloperoxidase activity in lung and liver --- p.46 / Chapter 2.7 --- Statistical analysis --- p.47 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Time-course experiment of acute pancreatitis model --- p.48 / Chapter 3.1.1 --- Effect of acute pancreatitis on tissue injury --- p.48 / Chapter 3.1.2 --- Effects of acute pancreatitis on oxidative status --- p.48 / Chapter 3.2 --- Evaluation of ramiprilat and saralasin on changes of acute pancreatitis- induced pancreatic injury --- p.50 / Chapter 3.2.1 --- Changes in tissue injury and histopathology --- p.50 / Chapter 3.2.2 --- Changes in oxidative status --- p.57 / Chapter 3.3 --- Evaluation of losartan and PD123319 on changes of acute pancreatitis- induced pancreatic injury --- p.61 / Chapter 3.3.1 --- Changes in tissue injury and histopathology --- p.61 / Chapter 3.3.2 --- Changes in oxidative status --- p.68 / Chapter 3.4 --- Evaluation of acinar secretions of digestive enzymes --- p.71 / Chapter 3.4.1 --- Cholecystokinin octapeptide-induced acinar secretions --- p.71 / Chapter 3.4.2 --- Angiotensin II-induced acinar secretions --- p.71 / Chapter 3.4.3 --- Effects of losartan and PD 123319 on α-amylase secretion --- p.74 / Chapter 3.5 --- Existence and regulation of acinar RAS by acute pancreatitis --- p.75 / Chapter 3.5.1 --- Expression of angiotensinogen and its regulation by acute pancreatitis in acini --- p.76 / Chapter 3.5.2 --- Expression of AT1 receptor and its regulation by acute pancreatitis in acini --- p.76 / Chapter 3.5.3 --- Expression of AT2 receptor and its regulation by acute pancreatitis in acini --- p.76 / Chapter 3.5.4 --- Evaluation of RAS inhibitors in acute pancreatitis-induced acinar cells --- p.80 / Chapter 3.6 --- Preliminary data on acute pancreatitis-induced systemic inflammation --- p.81 / Chapter 3.6.1 --- Time-course experiment on lung injury --- p.81 / Chapter 3.6.2 --- Time-course experiment on liver injury --- p.83 / Chapter 3.6.3 --- Evaluation of losartan on systemic inflammation --- p.85 / Chapter Chapter 4 --- Discussion / Chapter 4.1 --- "Actions of RAS inhibitors on the changes of tissue injury, oxidative status and histopathology in acute pancreatitis-induced pancreas" --- p.87 / Chapter 4.1.1 --- Differential effects of ramiprilat and saralasin --- p.88 / Chapter 4.1.2 --- Differential effects of losartan and PD123319 --- p.92 / Chapter 4.2 --- Potential functions of RAS in pancreatic acinar secretions --- p.95 / Chapter 4.2.1 --- Potential role of AT1 receptor --- p.96 / Chapter 4.2.2 --- Potential role of AT2 receptor --- p.98 / Chapter 4.3 --- Regulation of RAS in acute pancreatitis-induced acini --- p.98 / Chapter 4.3.1 --- Regulation of RAS components in acinar cells --- p.99 / Chapter 4.3.2 --- Differential actions of losartan and PD123319 --- p.100 / Chapter 4.4 --- Potential role of RAS in acute pancreatitis --- p.102 / Chapter 4.4.1 --- Regulation of RAS components by acute pancreatitis --- p.102 / Chapter 4.4.2 --- Differential functions of AT1 and AT2 receptors in acute pancreatitis --- p.103 / Chapter 4.5 --- Conclusion --- p.104 / Chapter 4.6 --- Further studies --- p.105 / Chapter Chapter 5 --- Bibliography --- p.107

Amiodarone (AM) is a potent antidysrhythmic agent which can cause potentially life-threatening pulmonary fibrosis, and N-desethylamiodarone (DEA) is a metabolite of AM that may contribute to the toxicity of AM in vivo. Recent evidence has implicated the involvement of the renin-angiotensin system (RAS) in the initiation and progression of amiodarone-induced pulmonary toxicity. In cultured HPL1A human peripheral lung epithelial cells, we found AM to be converted to DEA minimally (< 2%) after 24 h of incubation, indicating that the HPL1A cell culture model can be used to study the effects of AM and DEA independently. Apoptotic cell death was assessed by annexin-V-FITC (ann-V) staining and by terminal deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphate nick-end labeling (TUNEL), while necrotic cell death was determined by propidium iodide (PI) staining. The percentage of PI positive cells increased over six-fold after 24 h treatment with 20 μM AM (80.8%) compared to control (12.0%), and doubled after 24 h treatment with 3.5 μM DEA (20.4%) compared to control (10.8%). The percentage of ann-V positive cells decreased from 8.26% (control) to 1.56% following 24 h treatment with 10 μM AM and more than doubled after 24 h incubation with 3.5 μM DEA (22.0%) compared to control (9.86%) (p<0.05). Treatment for 24 h with 5.0 μM DEA caused the percentage of TUNEL positive cells to increase from 4.21% (control) to 26.7% (p<0.05). Vitamin E (5 – 20 μM) did not protect against AM or DEA cytotoxicity, as determined by ann-V and PI dual staining. Angiotensin II (100 pM – 1 μM) alone or in combination with AM or DEA did not alter cytotoxicity. Furthermore, the angiotensin converting enzyme inhibitor captopril did not protect against AM or DEA cytotoxicity. In conclusion, in vitro, AM activates primarily necrotic pathways, whereas DEA activates both necrotic and apoptotic pathways, and the RAS does not seem to be involved in AM or DEA cytotoxicity in HPL1A cells. Multiple mechanisms may contribute to the initiation of lung damage observed clinically, due to actions of both AM and its metabolite DEA. Keywords: amiodarone, desethylamiodarone, vitamin E, renin-angiotensin system / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-11-26 13:57:09.65

Thesis (Ph. D.)--Washington State University, August 2008. / Includes bibliographical references.

Thesis (doctoral)--Rijksuniversiteit te Groningen.

No description available.

The prevailing paradigm is that cardiac ANG II is synthesized in the extracellular space from components of the circulating and/or local renin-angiotensin system. The recent discovery of intracrine effects of ANG II led us to determine whether ANG II is synthesized intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent angiotensin type 1 (AT1) receptor-mediated internalization of ANG II. ANG II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized ANG II, respectively. Isoproterenol increased ANG II concentration in cell lysates and medium of NRVM in the absence or presence of candesartan. High glucose markedly increased ANG II synthesis only in cell lysates in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin, and chymase in high-glucose-exposed cells. Confocal immunofluorocytometry confirmed the presence of ANG II in the cytoplasm and nucleus of high-glucose-exposed NRVM and along the actin filaments in isoproterenol-exposed cells. ANG II synthesis was dependent on renin and chymase in high-glucose-exposed cells and on renin and angiotensin-converting enzyme in isoproterenol-exposed cells. In summary, the site of ANG II synthesis, intracellular localization, and the synthetic pathway in NRVM are stimulus dependent. Significantly, NRVM synthesized and retained ANG II intracellularly, which redistributed to the nucleus under high-glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions.

No description available.