No description available.

No description available.

Reabsorbing ~7% of the sodium load, the distal convoluted tubule plays key roles in blood pressure (BP) homeostasis. Here, Na-Cl co-transport (NCC) is the major route for apical Na entry making thiazide diuretics (NCC inhibitors) a mainstay hypertension treatment. Predictive adaptations of sodium excretory rhythms are supported by an intrinsic renal clock, which regulates transporter activity according to physiological need. Peripheral clocks can be influenced by glucocorticoids, which also have a circadian rhythm. We therefore hypothesized that NCC’s diurnal rhythm is regulated by glucocorticoids. C57BL6 mice were kept on a 12h light cycle with subjective day starting at 7am. Urine was collected in 12h periods and kidneys harvested at 1am (night) and 1pm (day). Slc12a3 (NCC encoding gene) mRNA and NCC protein abundance were similar between day and night but NCC phosphorylation at threonine 53 was significantly higher at night compared to day. Plasma and urinary corticosterone levels were elevated at night. Glucocorticoid inducible leucine zipper (GILZ) and serum and glucocorticoid inducible kinase (SGK1) transcripts also increased at night. Chronic corticosterone infusion flattened the plasma corticosterone rhythm within an intermediate physiological range. The diurnal rhythm of pT53 NCC was dampened in these mice but not in vehicle-treated mice. Blood pressure was monitored in the mice by radiotelemetry. After 2 weeks of baseline measurements mice received chronic corticosterone or vehicle for 3weeks, during the last 10 days of which they received ~80 mg/kg hydrochlorothiazide in their drinking water. At night systolic BP (SBP) was unaffected by any treatment whereas during the day SBP significantly increased following corticosterone but was unaffected by vehicle. Cosinor analysis of SBP in corticosterone and vehicle treated mice showed a marked reduction in rhythmicity, increased MESOR and reduced amplitude. In animals receiving corticosterone HCTZ partially rescued daytime SBP. This manoeuvre also improved SBP rhythmicity, reduced MESOR and increased amplitude. These data indicate that NCC phosphorylation has a diurnal rhythm that is in part regulated by glucocorticoids. They also show that alteration of the glucocorticoid rhythm affects the blood pressure rhythm in part through its effect on NCC phosphorylation. These findings may be clinically relevant in the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels such as metabolic syndrome and chronic stress.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

No description available.

Includes bibliographical references and index.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Cardiovascular disease (CVD) such as hypertension and stroke are serious illnesses that impact on the lives of millions all over the world, with 972 million (26% of the world’s population) suffering from hypertension in year 2000, and an estimated 1.56 billion to be affected by 2025. Hypertension, being one of the most common CVD is associated with the development of stroke, peripheral vascular diseases, myocardial infarction, renal failure as well as cardiac failure. Several studies have shown a seasonal correlation for both the systolic and diastolic blood pressure in mankind. A hypertension trial done by the Medical Research Council in the 1980s showed the average blood pressure being lower in summer than winter, and this difference was more significant in the elderly than the younger population. Other than seasonal variation, blood pressure (including hypertension prevalence) is also noted to correlate with latitude, being higher at places further away from the equator. Other cardiovascular related diseases such as stroke and acute coronary syndrome are also shown occur more frequently in winter. The morbidity and mortality of CVD could be due to various factors including diet, culture, race and social status, but within the United Kingdom, all cause mortality (with cerebral-vascular disease being the major one) correlates with latitude even after accounting for all known risk factors, with CVD risks highest in the north. We propose that this difference in cardiovascular mortality is caused by variations in ultraviolet exposure other than temperature. Known mechanisms of sunlight exposure that affect cardiovascular health include temperature and the ultraviolet B (UVB) mediated photolysis of 7-dehydrocholesterol in the skin to produce 1,25 dihydroxycholecalciferol (Vitamin D). UVB is however a potent skin carcinogen, and calculating risk-benefit ratios for exposure will be important. We believe that independently of vitamin D, nitric oxide plays an important role in blood pressure regulation and cardiovascular health, accounting for seasonal and latitude variation. In 1961, Furchgott demonstrated relaxation of rabbit aorta by irradiating them with ultraviolet light, and in later research he noted this effect is most significant in the ultraviolet A (UVA) spectrum. Recently, Mowbray showed a rich store of various nitro-species within human skin and Oplander showed a reduction of blood pressure in human after giving whole body UVA irradiation. We therefore hypothesize that independently of vitamin D, NO mediates the UVA induced beneficial effects on cardiovascular health. To support our hypothesis, in vivo as well as in vitro studies were conducted. We recruited a total of 63 healthy volunteers and monitored blood pressure, forearm blood flow as well as other cardiovascular parameters before and after UVA irradiation. Blood samples were also taken for the measurement of circulatory nitro-species. We have noted a significant reduction of blood pressure (from 84.5±1.76 to 81.33±1.37 mmHg) and increased forearm blood flow (1.95±0.28 to 2.94±0.47 mL/100mL of tissue/min) after UVA irradiation of human skin; simultaneously, we also noted a rise in circulatory nitrite (0.5±0.04 μM before irradiation to 0.72±0.04 μM) and a drop in circulatory nitrate (11.79±0.64 μM before irradiation and 8.99±0.4 μM). For us to further clarify the role of nitric oxide in different latitude, a monochromator machine that generates specific wavelength of light was been used to irradiate aqueous nitrite solution, and the total amount of nitric oxide release at different latitude was then calculated according to the irradiance of various wavelength across the globe. The results of our studies provide evidence suggesting that nitric oxide release induced by UVA irradiation of the skin can account for the difference in cardiovascular mortality and morbidity by latitude. The current public health advice of avoiding sun exposure to reduce the risk of developing skin cancer may need to be modified.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: School of Pharmacy. Title from title-page of electronic thesis. Bibliography: leaves 136-149.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.