This investigation studied the physiological means by which myocardium can survive and function properly when oxygen supply is limited and cannot initially match oxygen demand. The effects of isoproterenol (ISO) stimulations during low coronary perfusion pressure or hypoxemia on myocardial oxygen demand, work, and oxygen utilization efficiency were investigated.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pharmacology / Master / Master of Philosophy

No description available.

No description available.

A Thesis submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, for the Degree of Master of Science JOHANNESBURG 1986 / The adenosine deaminase enzyme from a Xhosa tribesman has been characterized. Red blood cell activity levels were 6-9% of normal whereas his white cell ADA levels were about 30% of normal. The enzyme's stability at 57°C was shown to be greatly reduced suggesting a mutation resulting in an enzyme with reduced stability in vivo. It was concluded that the discrepancy in ADA activity levels between red and white blood cells was due to the red cells being anucleate. The proband's residual ADA was found to have a Michaelis Constant (K ) for adenosine m of 47.9 ♦ IS.BuM, a value which is not significantly different from that of normal ADA (51.7 ± 11.4ufl). Red cell deoxy-ATP levels were measured and found to be elevated two-to-three times over normal levels. Red cells from ADA-deficient patients with severe combined immunodeficiency (SCID) have been reported with deoxy-ATP levels elevated about 1 000 times. It was concluded that the slight elevation of deoxy-ATP levels in the proband were too low to have any noticeable effect on functions of his immune system. Starch gel electrophoresis of red cell ADA from members of the proband's family in conjunction with red cell ADA activity levels suggested that both parents carried a gei e for 'partial' ADA deficiency, both of which had been inherited by the proband as well as one of his sibs. Isoelectric focusing studies suggested that the two, parental AUA partial deficiency genes were different from one another. It was also found that another rare allele of ADA, possibly ADA ',was segregating within the same family although this event appaars to be unconnected with the ADA partial deficiency.

Chapter 1 of thesis is a literature review of adenosine research. The central importance of the contributions of both classical pharmacology and, more recently, molecular biology to adenosine research is demonstrated. These disciplines have enabled the classification and characterisation of adenosine receptors and as well an understanding of the physiological significance of endogenous adenosine. The significant benefits of developing therapeutics for regulation of the diverse physiological functions of adenosine, by regulation of adenosine receptors, is outlined. For this therapeutic potential to be realised both high affinity and subtype selective adenosine agonists and antagonists are required. The structure-activity relationships for agonists and xanthine antagonists are discussed. The assimilation of these structure-activity relationships have guided the development of ligand based models of the adenosine receptor pharmacophore. The 'flipped', 'N6-C8' and 'three binding domain' models were described. These models aim to direct the future design of high affinity and selective ligands for adenosine receptors. The development of receptor based models by modelling of the receptor-ligand complex is also presented. The main body of this thesis presents a study of the structure-activity relationships for pyrazolo(3,4-d) pyrimidines binding to adenosine Ai and A2a receptors. Prior to this study few non-xanthine adenosine antagonists had been well defined or optimised in terms of structure-activity relationships. However, the value of such ligands is immense, facilitating further definition of structural requirements for high affinity and selective adenosine receptor binding. These ligands should complement existing agonists and xanthine antagonists in developing an understanding of adenosine receptor binding. The experimental approach to development of the lead compound of this study, a-(6-(l'-carbamoylethylthio)- l-phenylpyrazolo(3,4-d)pyrimidin-4-ylthio)propanamide (5), is outlined in Chapter 2 of this thesis. 5 is substituted at C-4, C-6 and N-i of the pyrazolo(3,4-d)pyrimidine heterocycle. The experimental approach to optiniising 5 was approached in a rational manner, requiring an iterative approach i.e. design of generation I target compounds --synthesis -- biological evaluation -- structure-activity relationships -- design of generation II target compounds, etc. Chapters 3, 4 and 5 of this thesis describe this experimental approach as it relates to optimising the lead compound, 5, for adenosine receptor affinity and subtype selectivity. The importance of receptor interactions with multiple ligand domains, to achieve both potency and selectivity, was recognised so that optimisation of the C-4, C-6 and N-i substituents of the lead compound was targeted and achieved. Previous structure-activity studies with agonists and xanthine antagonists have concentrated on modifying a single ligand domain. Chapter 3 presents twelve generation I target compounds to examine C-4 and C-6 substituent structure-activity relationships. Chapter 4 presents twelve generation II target compounds to further examine C-4 and C-6 substituent structure-activity relationships. Chapter 5 presents sixteen generation ifi target compounds to examine N-I substituent structure-activity relationships. A major outcome from the research presented in these chapters was the development of highly potent and highly selective ligands for the adenosine A1 receptor subtype. a(4-Methylamino- I -phenylpyrazolo(3,4-d)pyrimidin-6-ylthio)hexanamide (29) was the most potent ligand at the Ai receptor identified in this study, and is one of the most potent Ai selective antagonists ever reported. 29 has an A1 K1 value of 0.745±0.045 nM and is 332-fold selective for the A1 receptor over the A2a receptor. a-(1-Phenyl-4-propylthiopyrazolo(3,4-d)pyrimidin-6-ylthio)butanainide (27) was the most selective ligand of this study. It is four orders of magnitude selective for the A1 receptor (up to 16900-fold), and one of the most selective antagonists ever reported. This high selectivity has been achieved with the maintenance of good A1 affinity (A1 K1 = 29.5±6.6 nM). These results prove the value of modifying multiple substituents of adenosine receptor ligands, generating ligands which bind with high potency and selectivity to adenosine Al receptors compared to adenosine A2a receptors.

Graduation date: 1998

Graduation date: 1996

Thesis (Ph. D.)--University of Oregon, 2006. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 93-99). Also available for download via the World Wide Web; free to University of Oregon users.