Women with preeclampsia have enhanced vascular reactivity to Angiotensin II (Ang II) and extensive vascular infiltration of neutrophils. The primary mechanism to enhance vessel reactivity is RhoA kinase that phosphorylates MYPT1 to inhibit myosin light chain (MLC) phosphatase. Therefore, MLCs remain phosphorylated and increase sensitivity to calcium. Neutrophils release reactive oxygen species (ROS), which can activate this pathway, so we hypothesized that neutrophils would enhance vessel reactivity to Ang II. Omental vessels from normal pregnant women were used to study vascular reactivity. Ang II dose response (0.001-10µM) was significantly enhanced with perfusion of neutrophils (<2000/mm3, activated with IL-8) or ROS. Addition of superoxide dismutase (SOD)/Catalase to quench ROS or 3µM Y-27632, a specific RhoA kinase inhibitor, blocked enhancement. Vascular smooth muscle expression of pMYPT1 and pMLC in cell culture was significantly increased by neutrophils or ROS. The increase was prevented by Y-27632. RhoA kinase activity assay showed a 3-fold increase in RhoA kinase activity in omental vessels treated with ROS. Similarly, ROS also enhanced vessel reactivity to another vasoconstrictor, norepinephrine, via RhoA kinase. In preeclamptic women, increased neutrophil infiltration is associated with increased vascular expression and production of matrix metalloproteinase-1 (MMP-1). MMP-1 activates protease activated receptor-1 (PAR-1), which could cause endothelial endothelin-1 release, so we considered a novel hypothesis that MMP-1 might cause vasoconstriction and enhance vessel reactivity to Ang II via PAR-1. Omental vessels perfused with activated MMP-1 (0.025-25ng/ml) showed dose-dependent vasoconstriction. Perfusion of activated MMP-1 (2.5ng/ml) significantly enhanced dose response to angiotensin II. MMP-1 mediated vasoconstriction and enhanced vessel reactivity to Ang II was abolished by co-perfusion of 10µM SCH-79797, a specific PAR-1 blocker, and by 5µM BQ-123, a specific endothelin-1 type A receptor blocker. These data are the first to show that activated neutrophils enhance vascular reactivity to Ang II via ROS and the RhoA kinase pathway. They are also the first to show that MMP-1 induces vasoconstriction and enhances vessel reactivity to Ang II. Thus, vascular neutrophil infiltration leading to ROS and MMP-1 generation could be an important mechanism for hypertension in preeclampsia.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Title: Analysis of Pharmacotherapy by patients with diagnosis of arterial hypertension Student: Vasiliki Kontou Tutor: Prof. RNDr. Jiri Vlcek, CSs Department of Social and Clinical Pharmacy, Charles University of Prague, Faculty of Pharmacy in Hradec Kralove Introduction: Arterial Hypertension (AH) is characterized by elevated blood pressure, which often leads to increased morbidity and mortality. AH divided into primary and secondary. Aim: In the theoretical part the aim is to analyse the etiopathogenesis, methods of diagnosis and the treatment strategies of arterial hypertension in the recent literature. In the experimental part the aim is to analyse the provisions of the above diagnosis of arterial hypertension. Method: During a six month period were collected 58 prescriptions with the diagnosis of arterial hypertension from a pharmacy that provided pharmaceutical care in the Greek village, Mytikas. Only one prescription for one patient was analysed. In the prescriptions were collected data on drugs, patients and physicians. Results: The pilot study included 58 prescriptions. Most patients were elderly, over 65 years old and 30% were in age 71 - 80 years. General practitioners prescribed 65% of the medical prescriptions. Most frequently prescribed ARBs with hydrochlorothiazide drugs (27%) and...

Bibliographische Beschreibung Schreiber, Juliane Untersuchung des Einflusses von Persönlichkeitscharakteristika und Bewältigungsstrategien auf den Blutdruck bei Essentieller Hypertonie Universität Leipzig, Dissertation 85 S.1, 85 Lit.2, 30 Abb., 7 Tab., 11 Anlagen Referat: Bluthochdruck nimmt aufgrund seiner weiten Verbreitung in der Bevölkerung und den schweren Folgeerkrankungen einen großen Stellenwert in Forschung und Klinik ein. Die Ursache für die Entstehung der häufigsten Form des Bluthochdrucks, der Essentiellen Arteriellen Hypertonie, ist bis heute unzureichend geklärt. Es gibt Erklärungsansätze, dass Hypertonie mit bestimmten Persönlichkeitsmerkmalen einhergeht. Andererseits existieren auch Beobachtungen, welche den Schluss zulassen, dass einige Charakterzüge als Risikofaktoren fungieren könnten. Ziel der vorliegenden Pilotstudie war es, einen Beitrag zur Rolle von Persönlichkeitsmerkmalen und Bewältigungsstrategien bei der Entstehung einer Essentiellen Hypertonie zu leisten. Die vorliegende Arbeit ist Teil einer übergeordneten Studie, die hierzu einen umfassenden Beitrag unter Einschluss von Genetik und Bildgebung des Gehirns leisten sollte. Es erfolgte die Diagnosesicherung einer Essentiellen Hypertonie basierend auf einer systematischen mehrmaligen Blutdruckmessung, verschiedenen Laborparametern zum Ausschluss anderer möglicher Ursachen einer arteriellen Hypertonie und einer eingehenden Anamnese. Als Hauptzielgrößen sollten neben den mittleren Blutdruckwerten vor allem Daten zu Depression, Lebenseinstellung, Ängstlichkeit, Umgang mit Ärger und Stress mittels einer Batterie von Fragebögen gewonnen werden. Hinzu kam die Erforschung der Persönlichkeitsdimensionen Neurotizismus, Extraversion, Offenheit für Erfahrungen, Verträglichkeit und Gewissenhaftigkeit. Anhand der Daten wurden die Teilnehmer in zwei Gruppen eingeteilt: Probanden mit (1) Essentieller Hypertonie sowie solche mit (2) normotonen Blutruckwerten. Bezüglich Geschlecht, Blutdruckwerten etc. erwies sich das Studienkollektiv im Hinblick auf die Bevölkerung als repräsentativ. Mit Hilfe dieser Daten konnten Gruppenvergleiche gezogen werden, des Weiteren wurden parametrische Korrelationen über die Gesamtgruppe der Probanden über mögliche Zusammenhänge zwischen verschiedenen Persönlichkeitsmerkmalen und systolischen bzw. diastolischen Blutdruckwerten durchgeführt. Die Auswertung der Hauptzielgrößen spricht dafür, dass bestimmte Persönlichkeitsfaktoren mit dem Merkmal „Essentielle Hypertonie“ assoziiert zu sein scheinen. Die vorliegenden Befunde stützen somit die Hypothese eines Zusammenhanges von Persönlichkeit und der Entwicklung einer Essentiellen Hypertonie, sollten jedoch auf Grund der geringen Stichprobengröße (n=49) vorsichtig interpretiert werden. ____________________ 1 Seitenzahl insgesamt 2 Zahl der im Literaturverzeichnis ausgewiesenen Literaturangaben

Magister Scientiae (Physiotherapy) - MSc(Physio) / Background: Hypertension is a risk factor for both cerebrovascular accidents and cardiovascular diseases, holistic and cost effective measure are called upon to reduce its impact on society. One of the methods advocated for achieving this is health promotion. Therefore, health professionals, including physiotherapists, are called upon to redirect their health care management approaches towards preventative care. Aim: The aim of this study was to determine the knowledge, attitude and practice as well as to explore the perceptions of physiotherapists regarding their role in the management of hypertension in Dar es Salaam, Tanzania.

Magister Public Health - MPH / Background: Hypertension (HTN) complications are one of the leading causes of disability and mortality worldwide, with increasing trends noted in Africa. The most neglected causes of uncontrolled HTN and its complications are unhealthy diets, excess alcohol consumption and physical inactivity. Adherence to recommended lifestyle modifications remains low in Zimbabwe. This study seeks to explore the factors influencing adherence to World Health Organisation (WHO) lifestyle modification recommendations in patients with hypertension at Parirenyatwa Hospital, Harare. Methodology: An analytic cross-sectional study design was utilized. 328 hypertensive patients aged at least 18, receiving care at Parirenyatwa Hospital were recruited into the study. A self-administered questionnaire was used to collect information on demographics, knowledge and adherence to WHO recommended lifestyle modifications from participants. Statistical Package for Social Scientists (SPSS) version 20 was used for data analysis. The Spearman test was used to test for linear correlation among variables and the 5-point Likert Scale was utilized to categorize the extent of practice of dietary and physical activity recommendations by WHO.

Hypertensive left ventricular hypertrophy (LVH) increases the risk for the development of heart failure with systolic chamber dysfunction. However, the exact mechanisms and hence best therapeutic approach to prevent this transition process is uncertain. One potential mechanism is through excessive β-adrenergic receptor (-AR) activation, but the risks of β-AR blocker therapy may outweigh the benefits. Since activation of -AR augments function of the renin-angiotensin-aldosterone system, I therefore explored whether mineralocorticoid receptor (MR) blockade prevents the transition from hypertensive LVH to systolic chamber decompensation produced by excessive β-AR activation, and the mechanisms thereof. The role of hypertensive LVH as a predisposing factor to systolic chamber decompensation post-myocardial infarction (MI) is controversial. In the present thesis I therefore also evaluated this question. The effect of spironolactone (SPIRO, 80 mg.kg-1.day-1), an MR blocker, on LV chamber remodelling and function was evaluated in spontaneously hypertensive rats (SHR) in whom decompensation was induced by administering a low dose of the -AR agonist, isoproterenol (ISO) for 4.5 months. ISO administration resulted in an increased urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, and a decreased LV relative wall thickness without further enhancing an increased myocardial norepinephrine (NE) release in SHR. ISO reduced LV systolic chamber function (decreased LV endocardial fractional shortening and the slope of the LV systolic pressure- volume relationship) without modifying intrinsic myocardial systolic function (as assessed from LV midwall fractional shortening and the slope of systolic stress-strain relationship). SPIRO abolished ISO-induced chamber dilatation, wall thinning and systolic dysfunction, but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, or myocardial NE release. These results suggest that MR activation, through load-independent effects, may be critical in mediating the transition from compensated hypertensive LVH to dilatation and LV systolic chamber dysfunction. In SHR, ISO increased myocardial matrix metalloproteinase (MMP)-2 activity (zymography) after only 4-5 days of administration, a change that was associated with MMP-2, but not TIMP expression. The increased MMP-2 activity persisted until 4.5 months of the study and these changes were prevented by SPIRO. At 4.5 months, ISO resulted in increased non-cross-linked, but not cross-linked myocardial collagen concentrations in SHR, an effect that was abolished by SPIRO. Although at 4.5 months ISO administration was not associated with an increased cardiomyocyte apoptosis (TUNEL), an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Neither ISO nor SPIRO influenced cardiomyocyte length (image analysis and flow cytometry) in SHR. Thus MR blockade may prevent the adverse effects of β-AR activation in hypertensive LVH through alterations in the cardiac interstitium and cardiomyocyte apoptosis. Six-to-seven months after ligation of the left anterior descending coronary artery, LV myocardial systolic function as assessed from % shortening of the non-infarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and % thickening of the posterior wall (echocardiography) was reduced in infarcted SHR (SHR-MI) (p<0.05), but not in normotensive Wistar Kyoto (WKY-MI) animals as compared to corresponding controls (SHR-Sham, WKY-Sham). This change in regional myocardial function in SHR-MI, but not in WKY- MI, occurred despite a similar degree of LV dilatation in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis (TUNEL) or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in resting global LV chamber systolic function (endocardial fractional shortening-FSend and end-systolic elastance [LV Ees] determined in the absence of an adrenergic stimulus), in the presence of an ISO challenge a reduction in LV Ees in SHR-MI compared to WKY-MI and SHR and WKY-Sham rats was noted (p<0.04). These data suggest that with chronic MI, the hypertensive heart is susceptible to development of viable tissue myocardial dysfunction, a change which cannot be attributed to excessive chamber dilatation, apoptosis or necrosis, but which in-turn, contributes toward a reduced cardiac adrenergic-inotropic reserve. The present thesis therefore suggests that MR blockade may prevent the transition from hypertensive LVH to systolic chamber decompensation, and that pre-existing hypertensive LVH increases the susceptibility to a depressed LV regional myocardial systolic function in the non-infarcted LV myocardium subsequent to MI, an effect that translates into a reduced inotropic reserve.

Hypertension is the major cause of cardio-vascular diseases and contributes to 13.5% of premature deaths worldwide. With a 10–year risk to develop organ damages estimated at 30%, severe hypertension exposes even more patients to premature death. Severe hypertension is a type of hypertension with systolic blood pressure ≥ 180mmHg and/or diastolic blood pressure ≥ 110 mmHg that may present with or without symptoms/signs or target organ damages, and may be classified accordingly as asymptomatic (without symptoms/signs) severe hypertension, hypertension urgency (with symptoms/signs, no target organ damage) or hypertension emergency (with target organ damage). Hypertension urgency and hypertension emergency are considered hypertension crisis. This study aimed to establish the socio-demographic and clinical characteristics of the patients who presented with severe hypertension at the Emergency Departments of two private hospitals of the Netcare Management (Pty) Limited in Johannesburg during the period from the 1st of January 2010 to 30th April 2011. These patients presumably receive quality health care and may not be expected to develop severe hypertension. Therefore, this study would contribute to efforts to identify patients at risk and those who may benefit from preventive measures. The methodology of this study was a retrospective, transversal and comparative study. One thousand and forty-two patients were included in the study. All of these participants had a medical aid cover or were able to pay for medical consultation at a private hospital. Data were collected from an electronic database, the Medibank™, and from manual patients’ registers kept in each hospital’s Emergency Department. Severe hypertension was found among 1.7% of all patients who presented to the studied emergency departments. Only 817 patients were classified in the different subtypes of SH. Asymptomatic severe hypertension was the most common (83.4%) type of severe hypertension and hypertension emergency was the least common (4.8%). At Mulbarton Hospital, 50.2% of severe hypertension patients were male and at Linksfield Hospital, 60.3% were female. Male patients were younger than female patients. White patients and elderly were mostly affected by severe hypertension in the studied population. Systolic blood pressures were similar among the different races and genders. Black patients had higher diastolic blood pressure compared to white patients. White patients were older and may have had a tendency of isolated systolic hypertension. Overall, the most common symptoms/signs in hypertension urgency were chest pains (46.4%), headache (34.0%) and epistaxis (11.3%). The most common target organ damages in hypertension emergency were stroke (58.9%), left ventricular failure/congestive cardiac failure (28.2%) and seizures (12.8%). None of the studied characteristics could be claimed predictors of hypertension crisis. Also, there was no association between seasons and days of presentation and onset of severe hypertension in each hospitals. Further studies are required to include other factors that are known to affect the occurrence of severe hypertension, such as co-morbidities, smoking, alcohol intake and poor adherence to medication by known hypertensive patients. Also, risk factors contributing to the occurrence of SH among younger black patients need to be analysed.

Faculty of Health Sciences School of Pharmacy 0107750d VANNIEKERKD@mweb.co.za / The prescription habits of general practitioners are continually under the scrutiny of ethical critics. There are numerous factors that influence a practitioner’s decision as to which antihypertensive agents to prescribe for the treatment of hypertension. As outlined in various international and national guidelines for the management of hypertension, the recommended treatment depends on ethnicity, current life-style, diet, smoking, age, gender, family history and possible underlying or secondary conditions such as diabetes mellitus, heart failure, isolated systolic hypertension, myocardial infarction, pregnancy, and evidence of coronary artery disease (CAD), stroke or peripheral vascular disease. Currently the control of blood pressure in patients with hypertension is far from optimal with over 70% of hypertensive patients being reported as having imperfect control. A number of factors related to the patient, the practitioner or the medication may explain the high incidence of inadequate blood pressure control. One possible explanation for the poor control of blood pressure may be that practitioners fail to comply with the guidelines. Hence the aim of my study was firstly to determine whether a practitioner’s decision as to which medication to prescribe in the treatment of hypertension is influenced by the Southern African Hypertension Society Guidelines. Secondly, in an attempt to assess the validity of the results of the primary analysis, the actual prescription habits (MediCross® database) were assessed and compared to the general practitioner’s recall of their prescription habits. Questionnaires were distributed to 320 MediCross® practitioners and prescription habits were identified and substantiated by the screening of an existing MediCross® database. I chose as my sample MediCross® general practitioners, as they are demographically representative of all major urban areas in South Africa; likely to be open-minded to supporting research and answering questionnaires (as MediCross® is part of a Clinical Research Site Management Organisation); and I had access to the database of the prescriptions made by MediCross® practitioners hence enabling me to fulfil my second objective. However, it must be kept in mind that these practitioners are representative of general practitioners in urban areas only (as the title of my research report indicates). My results show that 33.1% adhere to the guidelines (when a non-conservative definition of diuretics is used); 27% have heard of the guidelines and have a copy of them. When asked to give their own opinion however, 39% thought they adhered to the guidelines. The results also show that ACE inhibitors are the most commonly prescribed drug class for uncomplicated hypertension but a comparison to a MediCross® database, of which the quality is questionable, does not support this. As the response rate to the questionnaires was only 24.7%, these results are only a pilot study; however they suggest that few general practitioners use the guidelines or even have a copy of the guidelines. This pilot study suggests that the guidelines need to be distributed more widely. Furthermore the general practitioners that responded to the questionnaire indicated that the management of hypertension is difficult in that there is no single treatment regimen appropriate for all populations and each different patient. It was also their view that clinical guidelines for the management of hypertension should more accurately reflect the uncertainty of when to initiate treatment and individual variation if they are going to take these guidelines seriously and comply with them.

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / In groups of African ancestry, who have a high prevalence of “salt-sensitive, low-renin” hypertension, there is considerable uncertainty as to relevance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of primary hypertension. In the present thesis I explored the possibility that the RAAS, through interactions with environmental effects, contributes to blood pressure (BP) in this ethnic group. After excluding participants with aldosterone-to-renin ratios (ARR) above the threshold for primary aldosteronism, in 575 participants of African ancestry, I demonstrated that with adjustments for confounders, an interaction between ARR and urinary Na+/K+ (and index of salt intake obtained from 24-hour urine samples) was independently associated with BP (p<0.0001). This effect was accounted for by interactions between serum aldosterone concentrations and urinary Na+/K+ (p<0.0001), but not between plasma renin concentrations and urinary Na+/K+ (p=0.52). The interaction between ARR and urinary Na+/K+ translated into a marked difference in the relationship between urinary Na+/K+ and BP in participants above and below the median for ARR (p<0.0001 for a comparison of the relationships). Having demonstrated that circulating aldosterone concentrations may account for a substantial proportion of the relationship between salt intake and BP in this community sample, I subsequently assessed whether genetic factors contribute toward serum aldosterone concentrations. In 153 randomly selected nuclear families of African ancestry consisting of 448 participants without primary aldosteronism, with, but not without adjustments for plasma renin concentrations, independent correlations were noted for iii serum aldosterone concentrations between parents and children (p<0.05), with parent-child partial correlation coefficients being greater than those for father-mother relationships (p<0.05). Furthermore, after, but not before adjustments for plasma renin concentrations, serum aldosterone concentrations showed significant heritability (h2=0.25±0.12, p<0.02). No independent relationships between RAAS gene polymorphisms and serum aldosterone concentrations were observed. I also aimed to assess whether RAAS genes modify the relationship between cigarette smoking and BP in groups of African descent. However, as the impact of mild smoking on BP is uncertain, and in the community studied only 14.5% smoked and the majority of smokers were mild smokers (mean=7.4±4.6 cigarettes per day) in 689 randomly participants I initially assessed the relationship between smoking habits and out-of-office BP. In this regard, current smokers had higher unadjusted and multivariate adjusted 24-hour systolic/diastolic BP (SBP/DBP in mm Hg) (p<0.005-p<0.0005) than non-smokers, effects that were replicated in sex-specific groups, non-drinkers, and in the overweight and obese. Current smoking was second only to age and at least equivalent to body mass index in the quantitative impact on out-of-office BP and the risk of uncontrolled out-of-office BP was increased in smokers as compared to non-smokers. Thus, despite minimal effects on in-office BP, predominantly mild current smoking was independently associated with an appreciable proportion of out-of-office BP in a community of African ancestry. In 652 participants I subsequently assessed whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism accounts for the strong relationships between predominantly mild smoking and out-of-office BP. After iv appropriate adjustments, an interaction between ACE DD genotype and current cigarette smoking, or the number of cigarettes smoked per day was independently associated with 24-hour and day diastolic BP (DBP) (p<0.05-0.005). This effect translated into a relationship between smoking and out-of-office BP or the risk for uncontrolled out-of-office BP only in participants with the DD as compared to the ID + II genotypes. In conclusion therefore, I afford evidence to suggest that in groups of African ancestry, aldosterone, within ranges that cannot be accounted for by the presence of primary aldosteronism, modifies the relationship between salt intake and BP, and that genetic factors account for the variation in serum aldosterone concentrations in this group. Furthermore, I show that the ACE gene modifies the relationship between smoking and out-of-office BP and hence accounts for even predominantly mild smoking producing a marked and clinically important effect on out-of-office BP. The present thesis therefore provides further evidence in favour of an important pathophysiological role for the RAAS in contributing toward BP in groups of African ancestry.