Tight control of blood glucose and blood pressure (BP) reduces cardiovascular risk in early Type 1 diabetes mellitus (T1DM). Increased BP normally increases renal medullary perfusion and sodium excretion. This is called acute pressure natriuresis. Inadequate acute pressure natriuresis disrupts circadian regulation of BP, which predicts hypertension. The peptide, endothelin-1 (ET-1), regulates BP via ETA and ETB receptors. ETA receptor antagonists reduce BP and restore its circadian rhythm. Two hypotheses were investigated. First, that acute pressure natriuresis is impaired in early T1DM, prior to established nephropathy, and this is associated with elevated BP. Second, that the mechanism is an ETA receptor-mediated blunting of medullary perfusion which can be reversed with insulin and ETA receptor antagonism. Experimental acute pressure natriuresis was induced in young, early T1DM (2-3 weeks post streptozotocin) Sprague Dawley rats and healthy controls. Despite maintaining glomerular filtration rate, early T1DM suppressed urinary flow (UV, 22.9±2.9 v. 93.7±11.1μl/min/gkw) and sodium excretion (UNaV, 3.2±0.7 v. 22.7±3.3μmol/min/gkw) rates by >80%, and reduced gradients of pressure diuresis (linear, 1.9 to 0.3) and natriuresis (non-linear k, 0.05 to 0.01) curves. Insulin treatment lowered blood glucose (16.8±1.8 to 9.3±0.6mmol/l) and restored gradients of the responses. Tissue and urine analyses did not suggest structural nephropathy. In early T1DM rats, changes in BP on radiotelemetry were consistent with impaired circadian regulation of BP and precursors of hypertension: 24-hour diastolic BP rose (92.3±0.4 to 97.1±0.5mmHg), and the circadian dip in diastolic BP fell (6±1 to 2±1%). Atrasentan (ETA receptor antagonist, 5mg/kg/day orally) reduced diastolic dipping in early T1DM (3±1 to 1±1%) while additional ETB receptor antagonism (A-192621, 10mg/kg/day orally) reversed this, suggesting that ETA, and not ETB receptors, mediate impairment of acute pressure natriuresis. To address this, renal blood flow was measured during experimental acute pressure natriuresis and ET receptor antagonism. Early T1DM suppressed the normal rise in medullary perfusion (flux, 227.2±26.7 v. 115.4±10.3%) by ~90%. Suppressed medullary flux was unaffected by insulin (112.2±6.8%), despite restoration of UV and UNaV. In controls, atrasentan reduced UV (15.7±4.9 v. 38.6±6.2μl/min/gkw), UNaV (1.7±0.5 v. 16.7±1.4μmol/min/gkw), FENa (3.4±1.4 v. 15.0±2.4%) and medullary flux (122.2±26.7%) by 60 to 90% of control values, while A-192621 increased UNaV (26.6±6.9μmol/min/gkw) and FENa (21.6±3.4%), but not medullary flux, by ~50%. ET receptor antagonism did not modify early T1DM+/-insulin effects. Diabetic status had no effect on renal ET-1 and ET receptor expression. These results support the first hypothesis but disprove the second. Early T1DM blunts medullary perfusion and acute pressure natriuresis, and increases diastolic BP. Insulin restores natriuresis but not medullary flow. Therefore, targeting medullary perfusion may reduce cardiovascular risk in early T1DM, but this is not achievable with selective ETA receptor antagonists. Novel natriuretic (ETA) and anti-natriuretic (ETB) roles for ET receptors, which are not apparent in early T1DM during severe, experimental rises in BP, appear to contribute to daily regulation of BP, and may preclude the use of selective ETA receptor antagonists in T1DM prior to nephropathy.

Thesis (M.S.)--University of Michigan, 1983.

Thesis (M.S.)--University of Michigan, 1983.

Objektiv: Psychosoziale Stressoren wurden seit langem für ihren Beitrag zur Entwicklung einer arteriellen Hypertonie untersucht, aber ihre Rolle dabei bleibt umstritten. In dieser Post-hoc-Analyse der bundesweiten Studie zur Gesundheit Erwachsener in Deutschland (DEGS1) wurden die Beziehungen von objektiv gemessenen Stressoren und selbst berichtetem Stresslevel auf den Blutdruck bestimmt. Methoden: Die Stichprobe der Studie umfasste 3352 Teilnehmer, die jünger als 65 Jahre alt waren, und derzeit in einem Beschäftigungsverhältnis standen und keine antihypertensive Medikation einnahmen. Der neu entwickelte Overall-Job-Index wurde zur Bewertung des arbeitsrelevanten Stressniveaus verwendet und der selbst wahrgenommene chronische Stress mit der Trierer Inventar zur Erfassung von chronischem Stress Screening-Skala (TICS-SSCS) gemessen. Ergebnisse: Bivariate Tests zeigten signifikante und negative Assoziationen zwischen dem durch TICS-SSCS gemessenen, selbst berichteten Stress mit dem systolischen (Schätzer = -0,16, Standardfehler [SE] = 0,03, p <0,001) bzw. diastolischen Blutdruck (Schätzer = -0.10, SE = 0,02, p <0,001), während der Overall-Job-Index positive signifikante Assoziationen für systolischen (Schätzer = 0,44, SE = 0,11, p <0,001) und diastolischen Blutdruck aufwies (Schätzer = 0,20, SE = 0,07, p = 0,005). Nach Adjustierung für Alter, Geschlecht und Body-Mass-Index blieb TICS-SSCS signifikant mit systolischem und diastolischem Blutdruck assoziiert, nicht aber mit dem Overall-Job-Index. Als Alkoholkonsum, Raucherstatus, körperliche Aktivität, Verkehrsdichte, sozioökonomischer Status, soziale Unterstützung, Pflege von Angehörigen und Leben in Partnerschaft als weitere Kovariablen zu den vorherigen Modellen zugegeben wurden, blieb TICS-SSCS weiterhin mit systolischem und diastolischem Blutdruck assoziiert (p = 0,007 und p = 0,001). Schlussfolgerungen: In einer großen und repräsentativen deutschen Studie wurde festgestellt, dass ein höher wahrgenommenes Stressniveau mit niedrigem Blutdruck assoziiert ist, während die in dieser Analyse untersuchten objektiven Stressfaktoren nicht signifikant mit Blutdruck korreliert waren. Diese Ergebnisse deuten darauf, dass Stress den Blutdruck auf verschiedenen Wegen beeinflusst und dass die Wahrnehmung von Stress das Ergebnis einer komplexen physiologischen Reaktionsantwort ist, die die Regulierung des Blutdrucks einschließt.

Visit-to-visit variability in blood pressure (BP) increases stroke risk, independent of mean BP. However, its physiological validity, the ideal method of measurement and the mechanisms increasing cardiovascular risk are unclear. In meta-analyses of individual patient data, I pooled associations between BP variability and risk of stroke, all cardiovascular events and death. I then determined antihypertensive drug-class differences in cardiovascular risk, intra-individual (I-VR) and inter-individual BP variability (M-VR). In 500 Oxford Vascular Study (OXVASC) patients undergoing thrice-daily home (HBPM) and awake ambulatory monitoring (ABPM), associations between mean, maximum or variability in BP (CV-BP) were determined with premorbid BP, hypertensive arteriopathy (creatinine, aortic stiffness, cognitive impairment, stroke versus TIA and leukoaraiosis) and cardiovascular events. In 200 patients, I determined associations with pulsatility or stiffness (pulse wave velocity) in cerebral and aortic vessels. There was a 21% and 27% increased risk of stroke and myocardial infarction per standard deviation of CV-SBP in 318700 patients, independent of mean SBP. In 244,479 patients, SBP variability was reduced by CCBs and diuretics within (I-VR=0.89, 95% CI=0.82-0.96, p=0.0001) and between individuals (M-VR 0.83, 0.77-0.89, p<0.0001), especially in the first year of treatment, explaining drug class differences in stroke risk (OR=0.76, 0.68-0.87, p<0.0001). In OXVASC, drug class differences on day-to-day SBP variability were greatest immediately after waking. Residual hypertension after treatment on HBPM but not ABPM (BP>135/85) predicted recurrent cardiovascular events (HR 2.82, 1.44-5.51, p=0.002 vs. 1.48, 0.68-3.23, p=0.33), reflecting stronger associations with premorbid BP and hypertensive arteriopathy, due largely to inaccuracy of ABPM in patients aged >65 years. Furthermore, day-to-day maximum and CV-SBP were associated with premorbid BP, hypertensive arteriopathy and cardiovascular events, with no additional predictive value of mean SBP when analysed with maximum SBP. Maximum SBP was greater in men and CV-SBP in women, whilst age and creatinine determined both. Increased stroke risk may partly be due to the association between BP variability and cerebral pulsatility, which was correlated with leukoaraiosis (p=0.01) and determined by aortic stiffness (p=0.016) and pulsatility (p<0.001). BP variability is clinically significant and physiologically valid, and is treatable with CCBs and diuretics. After TIA or minor stroke, HBPM best identifies residual hypertension and demonstrates the predictive value of BP variability and maximum BP, but associated arterial changes might explain some of the increased stroke risk.

Thesis (Ph. D.)--University of Florida, 2003. / Title from title page of source document. Includes vita. Includes bibliographical references.

Thesis (M.S.)--University of Michigan, 1988.

Thesis (M.S.)--University of Michigan, 1988.

Thesis (M.S.)--Brock University, 2005. / Includes bibliographical references (leaves 134-165). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M. Sc.)--Brock University, 2005. / Includes bibliographical references (leaves 134-165).