Doctor of Philosophy(PhD) / This thesis addresses the neurochemistry and function of specific nuclei in the autonomic nervous system that are crucial mediators of cardiorespiratory regulation. The primary aim is to build on previous knowledge about muscarinic cholinergic mechanisms within cardiorespiratory nuclei located in the ventrolateral medulla oblongata. The general focus is characterisation of gene expression patterns of specific muscarinic receptor subtypes in central nuclei involved in blood pressure control and respiratory control in normal rats. The findings were subsequently extended by characterisation of muscarinic receptor gene expression patterns in 1) a rat model of abnormal blood pressure control (hypertension) (Chapter 3) 2) a rat model of cholinergic sensitivity (Chapter 5) 3) the rat ventral respiratory group (Chapter 6) The results of a series of related investigations that ensued from the initial aims more finely characterise the neurocircuitry of the ventrolateral medulla, from a specifically cholinoceptive approach. All five muscarinic receptor subtypes are globally expressed in the ventrolateral medulla but only the M2R mRNA was significantly elevated in the VLM of hypertensive animals compared to their normotensive controls and in the VLM of animals displaying cholinergic hypersensitivity compared to their resistant controls. Surprisingly, M2R mRNA is absent in catecholaminergic cell groups but abundant in certain respiratory nuclei. Two smaller projects involving gene expression of other neurotransmitter / neuromodulators expressed in cardiorespiratory nuclei were also completed during my candidature. Firstly, the neurochemical characterisation of enkephalinergic neurons in the RVLM, and their relationship with bulbospinal, catecholaminergic neurons in hypertensive compared to normotensive animals was carried out (Chapter 4). A substantial proportion of sympathoexcitatory neurons located in the RVLM were enkephalinergic in nature. However, there was no significant difference in preproenkephalin expression in the RVLM in hypertensive compared to normotensive animals. Secondly, the identification and distribution of components of the renin-angiotensin aldosterone system (RAAS) within the brainstem, and differences in gene expression levels between hypertensive and normotensive animals was also investigated. The RAAS data was not included in this thesis, since the topic digresses substantially from other chapters and since it is published (Kumar et al., 2006). The mRNA expression aldosterone synthase, mineralocorticoid receptor (MR1), 12-lipoxygenase (12-LO), serum- and glucocorticoid- inducible kinase and K-ras) were found to be present at all rostrocaudal levels of the ventrolateral medulla. Expression of MR1 mRNA was lower in the RVLM of SHR compared with WKY rats and 12-LO mRNA levels were lower in the CVLM in SHR compared with WKY rats. Otherwise, there was no difference in gene expression level, or the method of detection was not sensitive enough to detect differences in low copy transcripts between hypertensive and normotensive animals.

<p>The aim of the work was to investigate the possibility to combine information from PPG and bio-acoustic technology to extract information that is related to the blood pressure. The measurements have been carried out with several different configurations. First the relation between arterial sounds and the PPG-signal was studied. After those measurements with both PPG and the bio- acoustic technique was concluded on people in different positions and after riding a bike. The goal was to vary the blood pressure. The conclusion that can be drawn in this report is that the bio-acoustic and the PPG-signal in peripheral arteries have the same source. That implies that arterial sounds are a product of turbulence when the pulse wave passes by. Further it can be assumed that it is the first heart sound that is represented in the arterial sounds. The time before and after the arterial sound in one heart cycle vary whit the blood pressure. There relationship seems also to vary with the bloodpressure but it vary differently under different conditions.</p>

<p>Kardiovaskulära sjukdomar och hypertoni blir allt mer vanligt i västvärlden. Trots livsstilsrekommendationer ökar antalet insjuknanden i hjärt-kärlsjukdomar, vilket har blivit en av de vanligaste dödsorsakerna i Sverige. Syftet med litteraturstudien var att undersöka om flavanol i kosten kan användas blodtryckssänkande samt att klargöra om flavanol påverkar den kardiovaskulära ohälsan. Metoden som användes var en litteraturstudie av redan publicerade vetenskapliga artiklar inom ämnet. Flertalet studier visar på att flavanol har en blodtryckssänkande likväl som andra positiva effekter. Många studiers resultat visar att flavanol har större effekt på de grupper som redan har kardiovaskulär ohälsa samt högt blodtryck. Forskningen är ny och har än inte hunnit utvärderas ordentligt, men den positiva påverkan hos flavanol är tydlig och det är inte svårt att se användbara områden för flavanol som terapeutisk metod, men även i hälsopromoterande syfte. Detta är något som skulle rimma väl med sjuksköterskans professionella ansvar att främja hälsa och motverka sjukdom. Trots de i dagsläget erhållna resultaten krävs mer och framför allt forskning med hög kvalitet.</p>

<p>Hypertoni är vanligt förekommande i dagens samhälle och anses därför ha blivit en folksjukdom. Uppskattningsvis har 1,8 miljoner av Sveriges vuxna befolkning hypertoni. Hypertoni står för cirka 13 procent av den totala dödligheten i världen, och ses som en riskfaktor till ett stort antal hjärt- och kärlsjukdomar. Idag finns det internationella riktlinjer för vård av hypertoni i bland annat England och USA. Dock saknas det specifika svenska riktlinjer för vård av hypertoni. Syftet med litteraturstudien var att belysa hur hälsofrämjande åtgärder kan påverka blodtrycket hos personer med hypertoni. Litteraturstudiens resultat bygger på en genomgång av 16 vetenskapliga artiklar som söktes utifrån litteraturstudiens syfte och problemformulering. De hälsofrämjande åtgärder som kan påverka blodtrycket hos personer med hypertoni belyses i resultatet. Dessa åtgärder handlar om viktminskning, fysisk aktivitet, kost, alkohol, rökning, stress och stöd. Effekten av de hälsofrämjande åtgärderna har visat att en blodtryckssänkning kan ske vid livsstilsförändringar. En bromsning i utvecklandet av hypertoni kan leda till hälsoekonomiska besparingar för samhället. Nationella riktlinjer samt vårdprogram för behandling av hypertoni bör utvecklas för att en bromsning av hypertoni ska kunna ske.</p> / <p>Hypertension is common in today's society and is therefore considered to have become a national disease. An estimated 1.8 million of Sweden's adult population have hypertension. Hypertension accounts for about 13 percent of the total mortality in the world, and is seen as a risk factor for numerous cardiovascular diseases. Today there are international guidelines for the treatment of hypertension in, England and USA. However, there are no specific Swedish guidelines for treatment of hypertension. The purpose of this study was to elucidate how health interventions can influence blood pressure in people with hypertension. The results of this literature study are based on a review of 16 scientific articles which was based on literature review and order problem. The health-promoting interventions that can affect blood pressure in people with hypertension are highlighted in the results. Such interventions are weight loss, physical activity, diet, alcohol, smoking, stress and support. The effect of health promotion interventions has shown that lowering blood pressure can occur if lifestyle changes are implemented and carried out. A braking in the development of hypertension can lead to health-economic benefits to the community. National guidelines and care programs for the treatment of hypertension should be developed to a braking of hypertension to happen.</p>

<p>This study examined relationships between 24-hour ambulatory BP and components of the insulin resistance syndrome, and investigated the prognostic significance of 24-hour BP for cardiovascular morbidity in a longitudinal population-based study of 70-year-old men. The findings indicated, that a reduced nocturnal BP fall, nondipping, was a marker of increased risk primarily in subjects with diabetes. A low body mass index and a more favourable serum fatty acid composition at age 50 predicted the development of white-coat as opposed to sustained hypertension over 20 years. Furthermore, cross-sectionally determined hypertensive organ damage at age 70 was detected in sustained hypertensive but not in white-coat hypertensive subjects. In a prospective analysis, 24-hour ambulatory pulse pressure and systolic BP variability at age 70 were strong predictors of subsequent cardiovascular morbidity, independently of office BP and other established risk factors. Isolated ambulatory hypertension, defined as having a normal office BP but increased daytime ambulatory BP, was associated with a significantly increased incidence of cardiovascular events during follow-up. </p><p>Hypertension constitutes part of the insulin resistance syndrome, and is a common and powerful risk factor for cardiovascular disease in elderly. Blood pressure (BP) measured with 24-hour ambulatory monitoring gives however more detailed information and may be a better estimate of the true BP than conventional office BP. </p><p>In summary, these data provide further knowledge of 24-hour ambulatory BP and associated metabolic risk profile, and suggest that the prognostic value of 24-hour ambulatory BP is superior to conventional BP in an elderly population.</p>

<p>The kidneys play a vital role in the maintenance of extracellular fluid and electrolyte balance and blood pressure. Adenosine, acting through the adenosine A₁-receptor (A₁R), and nitric oxide have been implicated in several of the regulatory mechanisms in the kidney. The A₁R has been found to be present in the renal vasculature, primarily in the afferent arterioles, and in the proximal tubules. The tubuloglomerular feedback mechanism (TGF) is an important regulator of renal vascular tone and glomerular filtration rate. The aim of these investigations was to further elucidate the role of adenosine, acting through the A₁R. Investigations on adenosine’s renal effects were performed on transgenic mice lacking the A₁R.</p><p>TGF response, elicited by increased distal salt load, was completely abolished in the A1R knockout (A₁R -/- ) mice. Basal plasma-renin levels were found to be ~2-fold higher in the A₁R -/- compared to the A₁R wild-type (A₁R+/+) mice. However, salt intake induced inverse changes in plasma-renin levels, indicating that adenosine tonically inhibits macula densa stimulated renin release. Anesthetized and conscious A₁R -/- mice, measured telemetrically, had an increased blood pressure, which could be due to the increased plasma-renin levels. Despite the high plasma-renin levels, increased urinary sodium excretion was also observed in the A₁R -/- animals. Ischemia caused a decrease in renal function in both A₁R+/+ and A₁R -/- mice. Ischemic preconditioning protected the A₁R+/+ mice from subsequent ischemic episode but had no protective effect on the A₁R -/- mice.</p><p>Acute extracellular volume expansion greatly attenuates TGF sensitivity, thus facilitating the elimination of excess fluid. Acute inhibition of nNOS in volume-expanded rats was found to re-establish the attenuated TGF response caused by acute extracellular volume expansion.</p><p>The results show that adenosine, acting through the A₁R, plays an important role in mediating TGF response and consequently, regulating renin release, blood pressure, electrolyte balance and other vital renal mechanisms.</p>

<p>Semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6) belongs to a family of copper-containing amine oxidases. SSAO exists as a membrane bound protein in endothelial-, smooth muscle-, and adipose cells as well as soluble in plasma. SSAO catalyses oxidative deamination of primary monoamines, which results in the production of corresponding aldehydes, hydrogen peroxide and ammonia. These compounds are very reactive and potentially cytotoxic, and are able to induce vascular damage if produced in high levels. Patients with diabetes mellitus, and with diabetic complications in particular, have a higher SSAO activity in plasma compared to healthy controls. It has therefore been speculated that high SSAO activity is involved in the development of vascular complications associated with diabetes. The aim of this thesis is to investigate the importance of SSAO in the development of disorders of a vascular origin. We have studied the transcriptional regulation of the SSAO gene, by inducing diabetes in NMRI and in transgenic mice, overexpressing the human form of SSAO in smooth muscle cells. We found that the increase in SSAO activity in diabetes is accompanied by reduced mRNA levels of the endogenous mouse gene, suggesting a negative feedback on the transcription of the SSAO gene. In addition, the transgenic mice exhibited an abnormal phenotype in the elastic tissue of aorta and renal artery. These mice have a lower mean artery pressure and an elevated pulse pressure. These results indicate that high SSAO activity in smooth muscle cells is associated with a change in the morphology of large arteries. This is likely contributing to the development of vascular complications in diabetes.</p>

Objectives To investigate if there is an association between dental health status and high blood pressure, to test the effectiveness of screening for high blood pressure and high blood glucose performed by the dental health care in collaboration with primary health care and to investigate the direct costs for this type of screening organisation. Study population and methods In Paper I 54 subjects with known hypertension and 141 with a high blood pressure in the dental office were compared with matched controls. In Paper II 1,149 subjects were screened for hypertension and in Paper III 1,568 subjects were screened for diabetes in dental care. Follow up was performed in co-operating primary health care centres. In paper IV the direct costs for screening and follow-up were calculated. Results There was a significant association between deep periodontal pockets and high blood pressure, even when the influence of age, sex, smoking and number of teeth was taken into account. Among those being screened for high blood pressure and high blood glucose 20.6% and 9.9% respectively were referred to primary health care, and a hypertension or a diabetes diagnosis was found in 32.1% and 5.8% of those screening positive. For every 18th subject screened a hypertension case was found (“numbers needed to screen” (NNS)), and for every 196th a diabetes case. NNS for combined hypertension and diabetes screening was 15. The total direct costs for screening and follow up per diagnosis found were 5,298 SEK for hypertension, 19,100 SEK for diabetes, and  4,116 SEK for combined blood pressure and blood glucose screening. Conclusions There was an association between dental health and hypertension. Screening for hypertension was highly efficient, while screening for diabetes was less so, because it is a less prevalent condition. Screening for both conditions appears to be the most efficient type of screening.

This study examined relationships between 24-hour ambulatory BP and components of the insulin resistance syndrome, and investigated the prognostic significance of 24-hour BP for cardiovascular morbidity in a longitudinal population-based study of 70-year-old men. The findings indicated, that a reduced nocturnal BP fall, nondipping, was a marker of increased risk primarily in subjects with diabetes. A low body mass index and a more favourable serum fatty acid composition at age 50 predicted the development of white-coat as opposed to sustained hypertension over 20 years. Furthermore, cross-sectionally determined hypertensive organ damage at age 70 was detected in sustained hypertensive but not in white-coat hypertensive subjects. In a prospective analysis, 24-hour ambulatory pulse pressure and systolic BP variability at age 70 were strong predictors of subsequent cardiovascular morbidity, independently of office BP and other established risk factors. Isolated ambulatory hypertension, defined as having a normal office BP but increased daytime ambulatory BP, was associated with a significantly increased incidence of cardiovascular events during follow-up. Hypertension constitutes part of the insulin resistance syndrome, and is a common and powerful risk factor for cardiovascular disease in elderly. Blood pressure (BP) measured with 24-hour ambulatory monitoring gives however more detailed information and may be a better estimate of the true BP than conventional office BP. In summary, these data provide further knowledge of 24-hour ambulatory BP and associated metabolic risk profile, and suggest that the prognostic value of 24-hour ambulatory BP is superior to conventional BP in an elderly population.

The kidneys play a vital role in the maintenance of extracellular fluid and electrolyte balance and blood pressure. Adenosine, acting through the adenosine A1-receptor (A1R), and nitric oxide have been implicated in several of the regulatory mechanisms in the kidney. The A1R has been found to be present in the renal vasculature, primarily in the afferent arterioles, and in the proximal tubules. The tubuloglomerular feedback mechanism (TGF) is an important regulator of renal vascular tone and glomerular filtration rate. The aim of these investigations was to further elucidate the role of adenosine, acting through the A1R. Investigations on adenosine’s renal effects were performed on transgenic mice lacking the A1R. TGF response, elicited by increased distal salt load, was completely abolished in the A1R knockout (A1R -/- ) mice. Basal plasma-renin levels were found to be ~2-fold higher in the A1R -/- compared to the A1R wild-type (A1R+/+) mice. However, salt intake induced inverse changes in plasma-renin levels, indicating that adenosine tonically inhibits macula densa stimulated renin release. Anesthetized and conscious A1R -/- mice, measured telemetrically, had an increased blood pressure, which could be due to the increased plasma-renin levels. Despite the high plasma-renin levels, increased urinary sodium excretion was also observed in the A1R -/- animals. Ischemia caused a decrease in renal function in both A1R+/+ and A1R -/- mice. Ischemic preconditioning protected the A1R+/+ mice from subsequent ischemic episode but had no protective effect on the A1R -/- mice. Acute extracellular volume expansion greatly attenuates TGF sensitivity, thus facilitating the elimination of excess fluid. Acute inhibition of nNOS in volume-expanded rats was found to re-establish the attenuated TGF response caused by acute extracellular volume expansion. The results show that adenosine, acting through the A1R, plays an important role in mediating TGF response and consequently, regulating renin release, blood pressure, electrolyte balance and other vital renal mechanisms.