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Wong Kwok Kui Wister. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 220-236). / ABSTRACT --- p.1 / OBJECTIVES FOR PROJECT --- p.4 / ABBREVIATIONS --- p.6 / Chapter CHAPTER 1 --- INTRODUCTORY LITERATURE REVIEWS / Chapter 1.1 --- Noradrenaline and adrenaline / Chapter 1.1.1 --- History --- p.8 / Chapter 1.2 --- The adrenal medulla / Chapter 1.2.1 --- The anatomy and microcirculation of the adrenal medulla --- p.10 / Chapter 1.2.2 --- Neuro-endocrine control of adrenal medullary secretion --- p.12 / Chapter 1.3 --- Dopamine / Chapter 1.3.1 --- Introduction --- p.14 / Chapter 1.3.2 --- Levels of DA in plasma and urine --- p.14 / Chapter 1.3.3 --- Origins of DA in the urine --- p.15 / Chapter 1.3.4 --- Control of renal DA production --- p.16 / Chapter 1.3.5 --- The actions of DA in the body --- p.17 / Chapter 1.3.6 --- The DA hypothesis --- p.17 / Chapter 1.3.7 --- Urinary NA and AD --- p.18 / Chapter 1.4 --- ACE inhibitors / Chapter 1.4.1 --- Brief review of the pharmacology of ACE inhibitors --- p.19 / Chapter 1.5 --- Catecholamine assays / Chapter 1.5.1 --- Introduction --- p.21 / Chapter 1.5.2 --- Chemistry --- p.22 / Chapter 1.5.3 --- Bioassay --- p.23 / Chapter 1.5.4 --- Colorimetry --- p.25 / Chapter 1.5.5 --- Fluorometry --- p.25 / Chapter 1.5.6 --- Radiochemical techniques --- p.27 / Chapter 1.5.7 --- Radioimmunoassay --- p.29 / Chapter 1.5.8 --- Chromatography --- p.30 / Chapter CHAPTER 2 --- METHODS - DEVELOPMENT OF A CATECHOLAMINE ASSAY & STABILITY STUDIES ON CATECHOLAMINES / Chapter 2.1 --- High performance liquid chromatography and electrochemical detection of catecholamines / Chapter 2.1.1 --- Introduction --- p.38 / Chapter 2.1.2 --- Basic equipment --- p.39 / Chapter 2.1.3 --- Stock aqueous CAT standards --- p.40 / Chapter 2.1.4 --- Mobile phase of HPLC-ECD --- p.40 / Chapter 2.1.5 --- Determination of mobile phase composition and flow rate --- p.41 / Chapter 2.1.6 --- Electrochemical detection --- p.43 / Chapter 2.1.7 --- Linearity and lowest detection limit of HPLC-ECD system --- p.49 / Chapter 2.1.8 --- Maintenance of HPLC-ECD system --- p.54 / Chapter 2.1.9 --- Discussion --- p.56 / Chapter 2.2 --- Sample pre-treatment & stability studies - Human urine / Chapter 2.2.1 --- Pre-treatment --- p.58 / Chapter 2.2.2 --- Analytical performance of the assay --- p.63 / Chapter 2.2.3 --- Stability studies --- p.85 / Chapter 2.2.4 --- Discussion --- p.101 / Chapter 2.2.5 --- Conclusions --- p.108 / Chapter 2.3 --- Sample pre-treatment & stability studies - Rat urine / Chapter 2.3.1 --- Pre-treatment --- p.111 / Chapter 2.3.2 --- Analytical performance of the assay --- p.111 / Chapter 2.3.3 --- Stability studies --- p.119 / Chapter 2.3.4 --- Discussion --- p.131 / Chapter 2.3.5 --- Conclusions --- p.133 / Chapter CHAPTER 3 --- "URINARY CREATININE, SODIUM AND POTASSIUM MEASUREMENTS" / Chapter 3.1 --- Introduction --- p.135 / Chapter 3.2 --- Method / Chapter 3.2.1 --- Urinary creatinine measurement --- p.135 / Chapter 3.2.2 --- Urinary sodium and potassium measurement --- p.136 / Chapter 3.3 --- Results / Chapter 3.3.1 --- Urinary creatinine measurement --- p.136 / Chapter 3.3.2 --- Urinary sodium and potassium measurement --- p.136 / Chapter 3.4 --- Discussion / Chapter 3.4.1 --- Urinary creatinine measurement --- p.136 / Chapter 3.4.2 --- Urinary sodium and potassium measurement --- p.137 / Chapter 3.5 --- Statistics --- p.138 / Chapter 3.6 --- Chemicals --- p.139 / Chapter CHAPTER 4 --- STUDIES ON URINARY EXCRETION OF CATECHOLAMINES IN MAN / Chapter 4.1 --- Population study on the relationships between dietary salt intake and urinary catecholamine output / Chapter 4.1.1 --- Introduction --- p.141 / Chapter 4.1.2 --- Method --- p.142 / Chapter 4.1.3 --- Results --- p.143 / Chapter 4.1.4 --- Discussion --- p.148 / Chapter 4.1.5 --- Conclusions --- p.149 / Chapter 4.2 --- The effect of oral salt loading on urinary catecholamine output / Chapter 4.2.1 --- Introduction --- p.149 / Chapter 4.2.2 --- Methods --- p.150 / Chapter 4.2.3 --- Results --- p.152 / Chapter 4.2.4 --- Discussion --- p.159 / Chapter 4.2.5 --- Conclusions --- p.161 / Chapter 4.3 --- The effects of perindopril on urinary catecholamine outputs / Chapter 4.3.1 --- Introduction --- p.162 / Chapter 4.3.2 --- Methods --- p.165 / Chapter 4.3.3 --- Results --- p.166 / Chapter 4.3.4 --- Discussion --- p.189 / Chapter 4.3.5 --- Conclusions --- p.190 / Chapter CHAPTER 5 --- STUDY ON URINARY EXCRETION OF CATECHOLAMINES AFTER ORAL ADMINISTRATION OF CAPTOPRIL TO RATS / Chapter 5.1 --- Introduction --- p.192 / Chapter 5.2 --- Methods --- p.192 / Chapter 5.3 --- Results --- p.193 / Chapter 5.4 --- Discussion --- p.210 / Chapter 5.5 --- Conclusions --- p.212 / Chapter CHAPTER 6 --- CONCLUSIONS --- p.214 / Chapter CHAPTER 7 --- FUTURE PROSPECTS --- p.216 / PUBLICATIONS TO DATE --- p.218 / ACKNOWLEDGEMENTS --- p.219 / REFERENCES --- p.220

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Pro-opiomelanocortin (POMC) is the precursor of many neuropeptides which includ adrenocorticotropin (ACTH). ACTH has a biological activity in regulating adrenocortical function. In the present study, we will investigate the effect of POMC gene transfer on adrenal cortex cells in cell cultures and animal models. The study included adrenal cortical H295R cells for adenovirus-mediated gene delivery. The effects of POMC gene on H295R cell steroidogenesis and cell proliferation were investigated. In addition, there were 32 SD rats dividing into three groups. 1) Control, injected with normal saline via tail vein (n = 8); 2) Ad-GFP, injected with adenovirus containing GFP (n=12); 3) Ad-POMC, injected with adenovirus containing recombinant POMC gene (n=12). Body weight (BW) was measured. Adrenals were collected, fixed and a series of sections were cut for stains for PCNA and MC2-R. The plasma cortisol and VEGF levels of rats were measured. The results showed that Ad-POMC delivery significantly increased the ACTH and cortisol levels by 50-100 fold and 20-100% in H295R cells, respectively. In addition, Ad-POMC delivery significantly inhibited the cell proliferation and increased the apoptotic cells. The expression of MC2-R protein of H295R cells was also suppressed after Ad-POMC delivery. In the study of SD rats, the Ad-POMC-treated rats exhibited reduced weight gain compared with other groups in the first 2 weeks; however, there was no significant change in BW between Ad-POMC and Ad-GFP groups during the experimental period. The weight of adrenal in Ad-POMC-treated rats was significantly higher than Ad-GFP group in the 8th week. Comparing the sequential adrenal weights in Ad-POMC group, those in 6th week were significantly higher than in 2nd and 4th weeks. The plasma VEFG levels of Ad-POMC-treated rats were higher than Ad-GFP group in the 8th week. The adrenal sections showed that Ad-POMC treated rats had moreanti-PCNA stained cells than Ad-GFP treated rats in 8th week. However, less anti-MC2R stained cells were found in Ad-POMC treated rats in 8th week. Ad-POMC treated rats had higher plasma cortisol levels than those in Ad-GFP treated rats, however, there were no statistical significances. In conclusion, POMC gene transfer modulates the morphology and function of the adrenal cortex. POMC gene inhibits the H295R cells proliferation by inducing MC2-R down-regulation and cells apoptosis. In SD rat adrenal, however, it stimulates adrenal cortex in biphasic pattern. The rapid growing pattern noted in the later phase may be due to the effect of VEGF. Besides, the physical regulation of cortisol synthesis is much stricter than that of ACTH.

This thesis describes metabolic changes occurring in chromaffin cells when secreting catecholamine (principally adrenaline), and the factors involved in maintaining the rate of secretion. In perfused pig adrenal glands, <sup>31</sup/>p nuclear magnetic resonance showed that nucleotide stored with catecholamine in the secretory vesicles (chromaffin granules) of the chromaffin cell was distinguishable from cytoplasmic nucleotide. Intragranular pH was 5.52 ± 0.15 (± SD, n=8) in ischaemic glands and rose (+ 0.22 ± 0.16 (± SD, n=6)) on recovery of cytoplasmic ATP during perfusion. This suggests that catecholamine accumulation by the granules is not driven by an ATP-generated pH gradient in intact tissue, as cytoplasmic ATP did not reduce intragranular pH. Perfused cortex-free ox adrenal medulla consumed 0.51 ± 0.19 (± SD, n=8) μmole 0₂/min/g wet weight after 210-230 minutes of perfusion, and this rose 30% during 4 minute O.lmM acetylcholine stimulations. This enhancement correlated with secretion but depended on the mode of stimulation, indicating that ATP consumption in secretion itself was an inadequate explanation. The proton-translocating Mg-ATPase of the chromaffin granule may hydrolyse ATP at its uncoupled rate on entering the plasma membrane during secretion by exocytosis. 1.4 ± 0.9 (± SD, n=12) moles of catecholamine were secreted per mole of enhanced oxygen consumption over 16 minutes. From this ratio, the oxygen consumption enhancement is shown to be much larger than that predicted from uncoupled proton pumping. Ouabain-sensitive oxygen consumption rose from < 6% to 18 ± 8% (± SD, n=4) during prolonged acetylcholine stimulation in the absence of calcium, suggesting that Na,K-ATPase was not responsible for all of the oxygen consumption enhancement. On continuous stimulation, secretion showed a biphasic decline in both pig and ox. A decline was also observed on intermittent stimulation. Cell death, potential-sensitive calcium gating and acetylcholine receptor desensitisation were only minor contributors. Little recovery occurred on resting the tissue for 2-3 hours between stimulations. The results are explained in terms of depletion of a pool of chromaffin granules adjacent to the plasma membrane.

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Thesis (Ph.D)--Biology, Georgia Institute of Technology, 2009. / Committee Chair: Marion B. Sewer; Committee Member: Alfred H. Merrill, Jr.; Committee Member: Donald F. Doyle; Committee Member: Dr. Edward T. Morgan; Committee Member: Kirill S. Lobachev. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1959. / Typescript. Abstracted in Dissertation abstracts, v. 20 (1959) no. 3, p. 1108-1109. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Human plasma contains cortisol (F) and corticosterone (B) at a ratio of ~10:1. B is well studied in mice and rats, which do not produce F due to absent adrenal Cyp17, but is largely neglected in humans. Differential transmembrane export of F > B by ABCB1 may account for accumulation of B in the CNS. Conversely, ABCC1, expressed in human adipose tissue, preferentially exports B>F. Here we tested the hypotheses that: (i) negative feedback suppression of the hypothalamic-pituitary-adrenal (HPA) axis is disproportionately sensitive to B; (ii) adipose tissue is disproportionately sensitive to F; and (iii) low plasma B contributes to impaired HPA axis negative feedback and increased F action in metabolic syndrome. We validated a stable isotope tracer for B in vitro and demonstrated distinct kinetics of B and F in vivo. In a randomised crossover study, we undertook ramped steady state infusion of B or F in 10 patients with Addison’s disease. Although levels of B were marginally lower than F, ACTH was similarly suppressed, and yet glucocorticoid-responsive transcripts in adipose tissue were much higher following F than B (PER1 2.2-fold and LPL 1.3-fold; p < 0.05). We assessed associations of ACTH-stimulated plasma B and F with features of metabolic syndrome in a cross-sectional study (n=279). Glucose tolerance was impaired with higher F (β=0.146, p=0.01) but lower B (β = -0.056, p = 0.05). These data support the concept of differential tissue sensitivity to B and F, whereby B suppresses the HPA axis more effectively than it induces adverse effects in adipose tissue. Enhanced CYP17 activity, causing ‘relative B deficiency’, may contribute to HPA axis activation and enhanced F action in adipose tissue in obesity. B therapy might allow control of HPA axis activation without inducing adverse metabolic effects. The ‘neglected second glucocorticoid’, corticosterone, may optimise glucocorticoid action in the human CNS, and simultaneously limit adverse metabolic effects driven by cortisol excess.

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