Hypertension (commonly known as "high blood pressure") is a disorder whose effects - either direct or indirect - are now widely recognized as capable of creating serious health problems in the segment of the population so affected. Estimates of the size of this segment depend on such factors as the criteria employed in the diagnosis of hypertension, but an overall figure of around 10% of the adult population is commonly quoted - along with the observation that the prevalence is greater among blacks, the elderly, and males in general. The major targets of hypertensive damage are the heart, the brain, the kidneys, and the retinae; consequently, heart attack and heart failure, stroke, and kidney failure are common causes of death among these patients. Unfortunately, the cause of the elevated arterial pressure can be "positively" identified in only some eight to twelve percent of all cases seen; the remaining patients are classified as "primary" or "essential" hypertensives. Research involving essential hypertension has been hampered by the complexity of the (as yet) poorly understood hemodynamic mechanisms of the body, and any sort of consensus here seems to be very slow in developing. Meanwhile, the disease is now being treated - upon discovery - with any one or a combination of three basic anti-hypertensive agents, all of which involve inconvenience, expense, and some rather unpleasant side effects. The wide-spread acceptance of these drugs has also had an unhappy effect on the evolution of our understanding of the clinical course of untreated hypertension, since now only the "mildest" cases may be studied in their natural form. Thus, many questions concerning hypertensive disease remain without satisfactory answers; an appreciation of the degree of uncertainty surrounding many of the issues may be had by examining the work of as few as three or four authors on the subject. Some of the unresolved (or only partially settled) issues include: the relative prognostic significance of the various signs and symptoms that are often associated with high blood pressure; the inter-relations that exist among these signs and symptoms; the pattern of change of the various symptoms over time and the relationship of such changes to the patient's outlook; and, finally, the nature and extent of the part played by hypertension within the broader problem of cardiovascular disease in general - and atherosclerosis in particular. Data on 48 male and 50 female primary hypertensives who received essentially no anti-hypertensive drug therapy, and who were followed until death (or for a maximum of ten years) are analyzed in this thesis, with the aim of illuminating the issues raised above - and others as well. Factors such as age, sex, blood pressure (average as well as extreme values), heart, brain, kidney, and retinal symptoms are examined, both in terms of their association with survival time as well as their inter-relations; sex differences and time trends are also explored. The bulk of the exploratory work is done with ordinary multiple regression and linear discriminant models. Considerable effort is devoted to attempts to reduce the instability that results from the presence of highly correlated variables within the prediction equation. Finally, the relatively new hazard function methodology proposed by Cox is used to obtain an objective and comprehensive formula for use in creating (or identifying) groups of patients who share a similar prognosis. Such a criterion would, for example, be helpful in designing a study to compare different forms of treatment of hypertension. / Science, Faculty of / Mathematics, Department of / Graduate

The Okamoto-Aoki strain of spontaneously hypertensive rats (SHR) is probably the most studied animal model of hypertension. Previous experience from our laboratory indicated that the vascular smooth muscle of the SHR is hyper-reactive to pressor agents in vitro, and that the sensitivity to calcium is also altered in these tissues. Since there is evidence for sodium ion and sodium pump abnormalities in erythrocytes of hypertensive patients and animals, the decision was made to use the erythrocyte membrane as a model for studying calcium-membrane interactions in the SHR. The Ca⁺⁺/Mg⁺⁺ ATPase activities (both high and low affinity) in the erythrocyte membrane from SHR were measured and found to be significantly elevated when compared to those of normotensive controls (WKY). Other erythrocyte membrane enzymes are not different between the two groups. Passive calcium influx into intact erythrocytes at 4°C was examined using ⁴⁵Ca as tracer and a significant increase in the passive permeability to calcium across the SHRs erythrocyte membrane was found when compared to the WKYs. Other abnormalities in the SHR erythrocyte include a reduction in osmotic fragility and increased levels of membrane cholesterol, phosphatidyl choline and sphingomyelin with marginal decreases in phosphatidyl ethanolamine and phosphatidyl serine. These findings indicate that structural and compositional alterations are present in the SHR erythrocyte membrane and these may be related to the increased passive permeability to calcium and the possibly compensatory increase in Ca⁺⁺/Mg⁺⁺ ATPase activity described earlier. Studies on the erythrocyte membranes of DOCA/salt hypertensive (DOCA) rats revealed no major differences in the activities of the membrane enzymes between the DOCA and nephrectomized controls (NC) animals. Furthermore, no difference was observed in passive calcium permeability between the erythrocytes from both groups of animals. Contrary to what was found in the SHR, osmotic fragility of the DOCA erythrocytes is slightly higher than that of NC's at all NaCl concentrations studied. No gross differences in membrane cholesterol and phospholipid profile were detected between the erythrocyte membranes from the two groups of animals'. These findings can be viewed as supportive evidence for the hypothesis that the membrane abnormalities observed in the SHR erythrocyte are probably genetically determined and not a consequence of elevated arterial pressure. In the third model of hypertension studied, rats were given increasing amounts of ethanol in their drinking water over period of 12 weeks, and a mild but significant (approx. 20%) elevation of systolic pressure was .observable beginning at week 4 and persisting through week 12. Urine ion analysis revealed that the ethanol-treated animals have reduced 24 hour urinary output and significant sodium retention. These findings prompted us to study the plasma volume in the animals using ¹⁴C-methyl-Y-globulins as an indicator. The plasma volume of the ethanol-treated animals averaged 20% higher than that of the control animals. Plasma catecholamine analysis revealed a significant increase in the levels of circulating noradrenaline in the ethanol-treated animals, but no differences in adrenaline and dopamine levels could be found when compared to controls. In vitro vascular smooth muscle responsiveness and erythrocyte membrane properties are not different between the two groups of animals. These results suggest that the mild blood pressure elevation in the ethanol-treated animals may be associated with both plasma volume expansion and elevated levels of circulating noradrenaline, and is probably not the result of. increased vascular responsiveness. Membrane alterations observed in SHR were not present in the erythrocytes of the ethanol-treated animals. To further investigate the confounding factors responsible for the blood pressure elevation in ethanol-treated animals, both controls and alcoholic animals were subjected to heat stress beginning at the 4th week of ethanol treatment, and a stratified distribution in the mean blood pressure is observed at week 12. The control unstressed (CU) animals have the lowest pressures, the control stressed ' (CS) animals have significantly higher pressures than CU groups, the alcoholic unstressed (AU) animals have the second highest pressure values, with the alcoholic 'Stressed (AS) having the highest mean blood pressure of all. Plasma volume is not different among the two control (CU, CS) and the two alcoholic (AU, AS) groups. The plasma noradrenaline levels correlated very well with the extent of blood pressure elevation and followed the same stratified distribution with CU animals having the lowest and AS animals having the highest levels. These results suggest that ethanol and stress may interact to produce hypertension, and that elevated plasma noradrenaline levels may play a role in the blood pressure elevation induced by stress. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

M.Tech.

Note:

Thesis (D. Sc.)--University of Adelaide, 1988. / Spine title. Includes bibliographical references.

Thesis (M.D. 1980) from the Department of Psychiatry, University of Adelaide.

Hypertension is a major cause of morbidity and mortality in communities of African ancestry. The most appropriate method of predicting the risk for blood pressure (BP)-related cardiovascular events is through 24-hour ambulatory BP (ABP) monitoring. Although the cost of monitors precludes the use of 24-hour BP measurement in groups of African descent in Africa, the extent to which BP-related cardiovascular risk may be underestimated by nurse-derived clinic BP measurements, and the current method of BP-related risk assessment in these communities, is uncertain. In this regard, nursederived BP measurement is thought to be superior to other forms of in-office BP measurement. Ambulatory 24-hour, day and night BP (SpaceLabs, model 90207) and nursederived clinic BP (CBP) (mean of 5 values) control rates were determined in 689 randomly selected participants (>16 years) of African ancestry in South Africa. Of the participants 45.7% were hypertensive and 22.6% were receiving antihypertensive medication. More participants had uncontrolled BP at night (34.0%) than during the day (22.6%, p<0.0001). However, uncontrolled CBP was noted in 37.2% of participants, while a much lower proportion had uncontrolled ABP (24.1%)(p<0.0001). These differences were accounted for by a high prevalence of isolated increases in CBP (whitecoat effects)(39.4%). Thus, in communities of African descent, despite a worse BP control at night than during the day, a high prevalence of white-coat effects translates into a striking underestimation of BP control when employing CBP rather than ABP measurements. Nurse-derived BP measurements are often as closely associated with organ damage as ABP. However, the extent to which relationships between nurse-derived BP measurements and organ damage reflect a white-coat effect (isolated increase in inoffice BP) as opposed to the adverse effects of BP per se are unknown. In 750 participants from a community sample, target organ changes were determined from carotid-femoral pulse wave velocity (PWV) (applanation tonometry and SphygmoCor software) (n=662) and left ventricular mass indexed to height2.7 (LVMI) (echocardiography)(n=463). Nurse-derived CBP was associated with organ changes independent of 24-hour BP (LVMI; partial r=0.15, p<0.005, PWV; partial r=0.21, p<0.0001) and day BP. However, in both unadjusted (p<0.0001 for both) and multivariate adjusted models (including adjustments for 24-hour BP)(LVMI; partial r=0.14, p<0.01, PWV; partial r=0.21, p<0.0001) nurse office-day SBP (an index of isolated increases in in-office BP) was associated with target organ changes independent of ambulatory BP and additional confounders. Thus, nurse-elicited whitecoat effects account for a significant proportion of the relationship between nursederived CBP and target organ changes independent of ambulatory BP. Therefore, high quality nurse-derived BP measurements do not approximate the impact of BP effects per se on cardiovascular damage. In 750 participants from a community sample I evaluated whether nurse officeday BP is inversely related to day-night BP (BP dipping) and whether this relationship may in-part explain the independent association between office-day BP and organ damage. Nurse office-day systolic BP (SBP) was correlated with % night/day SBP (r=0.22, p<0.0001) and night SBP (r=0.14, p=0.0001). Although unadjusted and multivariate adjusted (including for day SBP) nurse office-day SBP was associated with LVMI (partial r=0.15, p<0.01) and PWV (partial r=0.22, p<0.0001), neither day-night SBP (LVMI; partial r=-0.01, p=0.88, PWV: partial r=-0.04, p=0.30) nor % night/day SBP (LVMI; partial r=0.01, p=0.91, PWV: partial r=0.04, p=0.37) were independently related to target organ changes. Moreover, the relationships between nurse office-day SBP and target organ changes persisted with adjustments for either day-night SBP (p<0.05- p<0.0001) or night SBP (p<0.01-p=0.0001). Thus, although nurse office-day SBP, an index of an alerting response, is independently associated with an atttenuation of nocturnal decreases in SBP, neither a decreased BP dipping, nor nocturnal BP explain the independent relationship between nurse office-day SBP and target organ changes. Whether nurse office-day BP is affected by antihypertensive therapy, is uncertain. In the present study the effect of antihypertensive therapy on nurse office-day BP was assessed in 173 patients whom, off treatment, had a daytime diastolic BP ranging from 90 to 114 mm Hg. Over the treatment period marked decreases in BP occurred (p<0.0001). However, neither nurse office-day systolic (baseline=16.5±15.8 mm Hg, 4 months=15.3±18.9 mm Hg, p=0.49), nor diastolic (baseline=0.9±9.3 mm Hg, 4 months=4.3±10.7 mm Hg, p<0.005) BP decreased significantly from baseline. Thus, despite producing marked decreases in nurse-derived in-office and out-of-office ambulatory BP, antihypertensive therapy produces no change in nurse-elicited isolated increases in in-office BP (white coat-effects) in a group of African descent. In conclusion, the results of the present thesis indicate that in an urban, developing community of African descent, as compared to 24-hour BP measurements, nurse-derived BP measurements elicit a significant in-office increase in BP which translates into a marked underestimation of BP control at a community level; is strongly associated with organ damage through effects that cannot be attributed to 24-hour BP or to relationships with an attenuated decline in nocturnal BP; and which cannot be treated with antihypertensive therapy. Further work is required to assess the most cost-effective approach to excluding nurse-elicited isolated increases in in-office BP before initiating antihypertensive therapy to groups of African descent.

Thesis (Family Medicine)-- University of Limpopo, 2010. / Summary not available

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Hawaii at Manoa, 2005. / Includes bibliographical references (leaves 104-112).