Faculty of Health Sciencs School of physiology 0010633J bnkeh@uycdc.uninet.m / Blood pressure (BP) is a heritable trait. However, the loci responsible and the mechanisms by which these genes determine BP are uncertain. Based on widely published data regarding frequent phenotypic characteristics that exemplify essential hypertension (EHT) in persons of African ancestry, in the present thesis I explored the role of gene candidates most likely to contribute to BP in this group. In this regard a high frequency of persons of African descent experience increases in BP in response to an enhanced salt intake (salt-sensitive hypertension). In addition, many patients of African origin with EHT fail to respond to inhibition of angiotensin-converting enzyme (ACE) with an appropriate decrease in BP, a factor that cannot be explained entirely on the basis of reduced plasma renin levels in this group. Thus, I evaluated the role of several gene variants that could influence either renal salt handling or the activity and effects of the renin-angiotensin system on BP in subjects of African ancestry. Although the angiotensinogen (AGT) gene has at least 3 variants in the promoter region that influence angiotensinogen expression and which occur with a remarkably high frequency in populations of African ancestry, their role in this group is still controversial. To-date, interactions between these variants have not been considered. Using a casecontrol study design in a sample of 1325 subjects, as well as association analysis with 24 hour ambulatory BP (ABP) values in 626 hypertensives, I confirmed that an independent effect of functional AGT gene variants on the risk for EHT or 24 hour ABP was weak at best. Importantly, however, interactions between the -20A C and -217G A variants were noted to strongly impact on the risk for EHT as well as ABP. Furthermore, interactions between the -20A C and -217G A variants played a major role in iii contributing toward the variability of ABP responses to ACE inhibitors, but not calcium channel blockers in this population group, with genotype determining whether or not ACE inhibitor responses occurred. Although the 825C T polymorphism of the guanosine triphosphate (G) protein 3 subunit (GNB3) gene influences the activity of a substance that modifies renal salt handling, namely the Na+/H+ exchanger, its impact in hypertensives of African descent is controversial. In the present thesis I confirmed in a large sample that the GNB3 variant was not associated with the risk for EHT or ABP values in subjects of African ancestry. However, because the activity of the exchanger is enhanced in obesity I hypothesised that the GNB3 gene variant could mediate a clinically relevant BP effect by modifying the impact of body size on BP (type I or II genetic effect). Indeed, GNB3 genotype proved to be a strong determinant of the impact of body size on systolic BP values, with genotype determining whether or not the effect occurred. The epithelial sodium channel (ENaC) and atrial natriuretic peptide (ANP) have an important influence on renal salt handling. The T594M polymorphism of the -subunit of the ENaC gene only exists with a relatively high frequency in subjects of African ancestry. Previous studies conducted in this population group in relatively small samples have indicated that the ENaC and ANP gene variants determine BP in subjects of African descent. In a larger sample of subjects of African descent I demonstrated that the T594M polymorphism of the ENaC gene has no impact on BP in this population group. However, my results suggest that the ANP gene may be a candidate worthy of further study. In conclusion, the results described in this thesis provide evidence that lends some clarity to the role of likely gene candidates for BP control in people of African descent. iv Importantly, data from this thesis suggest that interactions between functional variants of specific loci (e.g the AGT gene), and clinically relevant type I or II genetic effects (no independent actions, but modifier gene effects, e.g, GNB3) should be considered before excluding loci as playing an important role in BP control. Moreover, this thesis provides the first substantial data to indicate that gene variants determine the variability of BP responses to pharmacological agents in hypertension in this population group.

Graham Neil Thomas. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (p. 245-281). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Background: Hypertension is one of the most common diseases in the United Kingdom and it remains an important risk factor for cardiovascular morbidity and mortality. Dietary sodium is an important trigger for hypertension and humans show a heterogeneous blood pressure (BP) response to salt intake. The mechanisms for this have not been fully explained, with renal sodium handling thought to play a central role. Animal studies have shown that dietary salt loading results in Na+ accumulation and lymphangiogenesis in skin mediated by vascular endothelial growth factor-C (VEGF-C), both attenuating the rise in BP. This represents an additional system for maintaining BP and volume homeostasis in response to salt load. The focus of this thesis is to determine whether these dermal mechanisms exist in humans. Methods: The technique of measuring skin Na+ and K+ using inductively coupled plasma optical emission spectrometry was developed in a pilot study of healthy adults. In a further study in healthy adults, the effects of dietary salt modulation on skin Na+, the effect of sex and the relationship between skin Na+ and haemodynamic parameters and plasma VEGF-C were studied. Skin Na+ concentrations were expressed as the ratio Na+:K+ to correct for variability in sample hydration. The effect of dietary salt intake on skin gene expression of factors that potentially influence BP such as VEGF-C and the hypoxia inducible factor (HIF) transcription system was assessed, exploring possible mechanisms linking skin Na+ to haemodynamic variables. Results: Skin Na+:K+ increased with dietary salt loading and this effect appeared to be greater in men while only women showed a rise in ambulatory mean BP. Skin Na+:K+ correlated with blood pressure, stroke volume and peripheral vascular resistance in men, but not in women. No change was noted in plasma vascular endothelial growth factor-C. Conclusions: These findings suggest that the skin may buffer dietary Na+, reducing the hemodynamic consequences of increased salt and this may be influenced by sex. Skin Na+ may influence blood pressure, stroke volume and PVR.

Hypertension is a complex multifactorial pathology that is a major risk factor for the development of cardiovascular disease, stroke, and end stage renal disease. In the United States, hypertension affects over 1 in 3 adults and comprises an annual cost of over $58 billion in the healthcare industry. While remarkable strides in the diagnosis and treatment of hypertension have been made since the pathology was first treated in the 1960s, a remarkable 13% of patients with elevated blood pressures are classified as resistant hypertensive, where blood pressure remains uncontrolled while on three or more classes of anti-hypertensive drugs. This treatment gap suggests that researchers need to develop and utilize translational models that recapitulate the pathologies seen in patient populations. Non-human primates (NHP) are highly similar to humans in terms of physiology, circadian rhythmicity, behavior, and gene sequence and structure. Development of NHP models that spontaneously develop pathologies, like spontaneous hypertension, provide novel and vital tools to studying disease. Overall, this dissertation is a comparative analysis of the mechanisms that drive the development of spontaneous hypertension in Chlorocebus aethiops sabaeus, an Old World non-human primate, and known mediators of essential hypertension in human populations. Chapter 2 presents how hypertensive (HT) African Green Monkeys (AGMs) are older, with elevated heart rates, increased renal vascular wall/lumen ratios, and altered glomerular morphologies compared to normotensive (NT) controls. Chapter 3 describes metabolic studies performed in a large cohort of animals that identified elevated proteinuria and ion excretion in HT AGMs compared to NT animals. Chapter 4 focuses on the contribution of sympathetic nervous system to the development of hypertension in this animal model and describes the significant left ventricular hypertrophy and elevation of adrenergic receptor mRNA in HT AGMs. Chapter 5 examines how age affects hypertension and renal function in the NT and HT AGMs. Together these data provide a foundational basis for the development of spontaneous hypertension in the AGM and provide a novel translational model for the study of cardiovascular disease.

Hypertension is a serious medical condition. Although men and women of all racial groups in the US suffer from high blood pressure, black women have the highest rates of hypertension. For instance, the age-adjusted prevalence of hypertension among black women ages 20 and over is 44.3, compared to 28.1 among white women, 40.5 among black men, and 31.1 among white men. Past research has focused on SES and behavioral factors as potential explanations for blood pressure disparities between black and white women. But, even after controlling for such factors, considerable disparities remain. The goal of this research is to examine cultural and social factors that have been shown to increase blood pressure. Specifically, I examine social support, psychosocial characteristics, and contextual factors associated with race/ethnicity and hypertension, in hopes of explaining some of the disparities in high blood pressure between black and white women. iii Using data from Waves I, III, and IV of the National Longitudinal Study of Adolescent Health (Add Health), I estimated a sequence of multinomial logistic regression models predicting prehypertension and hypertension in young adulthood. Cross-sectional models show that racial disparities in hypertension remain after controlling for social support, psychosocial characteristics, and contextual factors. In fact, the only covariate that substantially reduced the racial disparity in hypertension was body mass index (BMI), a fairly reliable measure of body fatness for most people. I also estimated a set of multinomial logistic regression models predicting odds of prehypertension and hypertension by adolescent and cumulative social support, as well as psychosocial, contextual, and behavioral factors. These models were included to determine if early life and/or cumulative factors and conditions would help explain racial blood pressure disparities not explained by adulthood factors. Findings show that none of the early life or cumulative social support, psychosocial, contextual, or behavioral factors helped to explain racial differences in prehypertension or hypertension. Even after controlling for these factors, black women are still 1.18 times more likely than white women to have prehypertension and over two times more likely to suffer hypertension. Indeed, my findings indicate that, of the factors included in all these models, only race, age, and BMI were significant predictors of blood pressure. Also, BMI was the only factor to explain some of the disparities between black and white women. These results are similar to other studies that have examined racial health disparities, suggesting that simply being a black woman in US society may be unhealthy. The health effects of racism, discrimination, and other sources of stress faced disproportionately by black women are not easily measured by social science research, which is possibly why racial disparities in blood pressure have yet to be explained. Future research should also explore possible epigenetic effects introduced by the health conditions experienced by previous generations, as well as the influence of prenatal and early life environments.

The epithelial sodium channel (ENaC) is the central component of the sodium absorption pathway in epithelia. It is critical for sodium homeostasis and blood pressure control, which is demonstrated by rare genetic disorders such as Liddle�s syndrome and pseudohypoaldosteronism type I, that are associated with hyper- and hypotension, respectively. ENaC is mainly regulated by mechanisms that control the expression of active channels at the cell surface. Ubiquitin ligases of the Nedd4-like family, such as Nedd4 and Nedd4-2 decrease epithelial sodium absorption by binding to and targeting ENaC for endocytosis and degradation. This is most likely achieved by catalyzing the ubiquitination of ENaC. Conversely the serum- and glucocorticoid regulated kinase (SGK) increases ENaC activity. This effect is partly mediated by the interaction of SGK with the ubiquitin ligases Nedd4 and Nedd4-2. SGK is able to bind to both Nedd4 and Nedd4-2, however only Nedd4-2 is phosphorylated by SGK. The phosphorylation of Nedd4-2 inhibits its interaction with ENaC, thus reducing ENaC ubiquitination, thereby increasing surface expression and sodium absorption. Nedd4-like proteins interact with ENaC via their WW-domains. These domains bind PY-motifs (PPXY) present in ENaC subunits. Nedd4 and Nedd4-2 both have four highly similar WW-domains. Previous studies have shown that interaction between Nedd4 and ENaC is mainly mediated by WW-domain 3. SGK also has a PY-motif; therefore it was analyzed whether the WW-domains of Nedd4 and Nedd4-2 mediate binding to SGK. Here, it is shown that single or tandem WW-domains of Nedd4 and Nedd4-2 mediate binding to SGK and that, despite their high similarity, different WW-domains of Nedd4 and Nedd4-2 are involved. These data also suggest that WW-domains 2 and 3 of Nedd4-2 mediate the interaction with SGK in a concerted manner, and that in vitro the phosphorylation of SGK at serine residue 422 increases its affinity for the WW-domains of Nedd4-2. The stimulatory effect of SGK on ENaC activity is partly mediated via Nedd4-2 and will decrease if competition between Nedd4 and Nedd4-2 for binding to SGK occurs. Here it is shown that Nedd4 and Nedd4-2 are located in the same subcellular compartment and that they compete for binding to SGK. Besides its function in the proteasomal degradation pathway ubiquitination is involved in the regulation of membrane protein trafficking, including their endocytosis. ENaC was shown previously to be ubiquitinated. Here, we provide evidence that ENaC can be ubiquitinated differentially depending on its cellular location. Channels residing in the plasma membrane are multiubiquitinated and we suggest that this serves as an internalization signal for ENaC and a control for further trafficking. Cytosolic ENaC is mainly polyubiquitinated, and therefore probably targeted for proteasomal degradation. However, mono- and multiubiquitination of ENaC located within the cytosol is very likely to occur as well. In addition, it is shown that both proteasomal and lysosomal pathways are involved in the regulation of ENaC.

The work reported in this thesis is an investigation of certain aspects of both the blood pressure (BP) elevating properties and BP lowering properties of arginine vasopressin (AVP). The hypothesis that endothelin (ET) contributes to the exaggerated pressor responsiveness of the spontaneously hypertensive rat (SHR) to AVP was tested by comparing the changes of BP, cardiac output (CO), and total peripheral conductance (TPC) to AVP in SHR to those in Wistar-Kyoto rats (WKY) both in the presence and absence of bosentan, a non-selective ET antagonist. Bosentan antagonized the BP responses to exogenous ET-1 in a competitive fashion. The pressor effects of AVP and Ang II were exaggerated in the SHR compared to WKY. Except for the highest dose of AVP, pre-treatment with bosentan blunted the increases in BP and the decreases in total peripheral conductance (TPC) evoked by AVP in the SHR, but not in the WKY. In contrast to AVP, bosentan blunted the increases in BP evoked by lower doses of Ang II in both strains, although the effect was more pronounced in the SHR. These results suggest that ET contributes to the hemodynamic effects of AVP in the SHR and to the effects of Ang II in both strains. The findings support the hypothesis that ET contributes to the exaggerated pressor responsiveness of SHR to AVP. Cessation of a 3 hour infusion of AVP (20 ng/kg/min) results in a dramatic and prolonged decrease in BP below pre-infusion basal levels in hypertensive rats, but not in normotensive control rats. This phenomenon has been termed the "withdrawal-induced antihypertensive phenomenon" (WAP). In order to determine the time course of the WAP, and the role of CO and TPC in the WAP, BP was recorded by radiotelemetry and CO was recorded from aonic flowprobes in conscious unrestrained rats before, during, and after a 3 hr i.v. infusion of 20 ng/kg/min of AVP. Baseline mean arterial BP values were lower, and the magnitude of the WAP was less in SHR when BP was recorded with radiotelemetric implants than in another group in which BP was recorded with conventional externalized femoral arterial catheters. Strikingly, absolute BP values recorded both during and after the AVP infusion were similar in the two groups. BP remained decreased for several days in SHR infused with AVP with complete recovery requiring 6-7 days. In rats instrumented with aortic flow probes, the fall in pressure following cessation of the AVP infusion was associated with a large decrease in CO below control levels in the SHR. The time-course of the CO responses approximated the time-course of the pressure responses. These results lead to the following conclusions: firstly, telemetry is a superior method for recording BP in hypertensive animals, and the lower magnitude of the WAP was probably related to the lower basal BPs recorded by this method; secondly, the mechanism accounting for the WAP must be of a long duration; thirdly, the WAP is mediated by a fall in CO and not by an increase in TPC. In conclusion, the results of the thesis support the hypothesis that ET contributes to the BP elevating properties of AVP and, consequently, the exaggerated pressor responsiveness of SHR to the peptide, and that the BP lowering properties of AVP are mediated by a fall in CO.

Aim: The aim is to create a review that examines different forms of massage therapy and their effects on hypertension. Method: Literature review of 10 scientific articles on the subject of massage and its effects on blood pressure. The literature searches were made with PubMed and Cinahl using the keywords "massage therapy", "effects" and "blood pressure". Results: The articles showed that massage had a positive effect in lowering blood pressure. This could be explained by greater extent of relaxation in the participants investigated and an increased activity of parasympaticus and reduced secretion of stress hormones. The articles do not agree on what form of massage therapy is most effective in lowering blood pressure and it is uncertain for how long the effect can remain. Conclusion: Massage is usually seen as a treatment without scientific basis. There is evidence that suggests that massage therapy is an effective treatment for lowering blood pressure. The articles show that different forms of massage effect blood pressure in various ways. However, a larger randomized controlled trial is needed to determine whether massage therapy can be used as a complement to medical treatment for hypertension and what form of massage is the most effective.

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Biomedical Engineering." Includes bibliographical references (p. 60-66).

Diss. (sammanfattning) Göteborg : Univ. , 2009. / Härtill 3 uppsatser.