Salt-sensitive hypertension, a key component of essential hypertension, affects approximately 50% of hypertensive patients and dramatically increases the risk of adverse cardiovascular events. Excess dietary sodium intake is an established cause of hypertension, but there remains no clear understanding of the central molecular pathways acting to facilitate sodium homeostasis and normotension in salt-resistant phenotypes, or potential derangements in these antihypertensive systems in salt-sensitive hypertension. Therefore, there exists a critical need to elucidate the neural mechanisms that account for the phenotypic difference between salt-resistance and salt-sensitivity. The current studies hypothesize that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the central responses activated to counter the development of salt-sensitive hypertension. Salt-resistant (Sprague-Dawley, Dahl salt-resistant, Brown Norway) and salt-sensitive (Dahl salt-sensitive, 8-congenic Dahl salt-sensitive) rat phenotypes were utilized to investigate the role of central Gαi2 proteins in the physiological regulation of blood pressure in response to acute and chronic challenges to sodium homeostasis. Salt-resistant animals remain normotensive following chronic high salt intake and exhibit an endogenous site-specific increase in PVN Gαi2 proteins. Exogenous oligodeoxynucleotide-mediated downregulation of Gαi2 proteins throughout the brain evokes rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation in animals typically salt-resistant. In salt-sensitive animals, Gαi2 protein downregulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Central Gαi2 protein downregulation also resulted in prolonged elevated blood pressure mediated by an attenuated activation of parvocellular PVN neurons. The PVN is the critical brain site at which the antihypertensive compensatory action of Gαi2 protein mediated signal transduction influences blood pressure regulation. PVN Gαi2 protein-mediated signal transduction represents a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. This also differentially influences PVN parvocellular neuronal activation, sympathetic outflow, and arterial pressure in response to sodium challenges, independently of actions on magnocellular neurons and vasopressin release. Impairment of this signaling mechanism contributes to the development of salt-sensitive hypertension. Collectively, this work highlights the complex interaction between the CNS and kidney, and the role of the sympathetic nervous system, in the short and long-term regulation of blood pressure.

Introduction: Hypertension is a complex disease that affects about 40% of adults worldwide, and is a major risk factor for cardiac hypertrophy and heart failure. Abnormal calcium handling plays a key role in hypertension and cardiovascular disease. In order to function normally cells of the cardiovascular system need to keep intracellular Ca2+ levels under tight control. This is achieved by a number of Ca2+ handling proteins including the plasma membrane Ca2+-ATPase (PMCA). Recent genome wide association studies have shown that single nucleotide polymorphisms in ATP2B1, the gene encoding PMCA1, are strongly linked with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: This thesis aims to examine whether there is a link between PMCA1 and blood pressure regulation, and the development of hypertension. It also aims to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1, a global PMCA1 heterozygous knockout mouse (PMCA1Ht) was used. Under basal conditions, 3 month old PMCA1Ht mice had about 50% reduction in PMCA1 protein expression compared to the wild type (WT) mice. PMCA1Ht and WT mice had similar blood pressure as measured by tail-cuff method. To study the mice under hypertensive stress conditions, 3 month old PMCA1Ht and WT mice were infused via minipump with angiotensin II. Upon angiotensin II treatment, PMCA1Ht mice showed a significantly greater increase in systolic and diastolic pressure compared to WT mice. Angiotensin II also induced vascular remodelling, with PMCA1Ht mice having greater media thickness and cross sectional area than WT mice. Moreover, PMCA1Ht mice showed a significantly greater cardiac hypertrophic response than WT mice. On the other hand, cardiac function and heart rate were similar in PMCA1Ht and WT mice. While angiotensin II had no effect on PMCA1 expression in the heart, it significantly increased PMCA1 expression in the aortas of both WT and PMCA1Ht mice. More importantly, WT mice had significantly higher PMCA1 expression level than the PMCA1Ht mice treated with the same dose of angiotensin II. This suggests that PMCA1 plays a pivotal role in Ca2+ extrusion in the vasculature and that under stressful conditions PMCA1Ht mice are less able to respond to stress through a compensatory increase in PMCA1 expression, leading to increased intracellular Ca2+ concentration, which in turn leads to increased vascular contractility and increased blood pressure. Conclusion: This work provides evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

Medicinal plants have long been used in folkloric medicine in various parts of the world. Presence of phenolic compounds has been attributed to their medicinal properties. Despite various medicinal uses, scientific claims of anti-hypertensive activities are still deficient. Therefore, hydroethanolic (70% ethanol) extracts of the leaf and root parts of T. officinale (TOL and TOR respectively) were investigated for anti-hypertensive antioxidant, diuretic activities, and effects on lipid profile in L-Name-induced hypertensive Wistar rats. Phytochemical screening of TOL and TOR was assessed by known standardized method. Acute toxicity profile of the plant was also evaluated by Lorke’s method. Total phenolic and flavonoid contents were assessed using Folin Ciocalteau and Aluminium chloride colorimetric methods; while, 2, 2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2’–azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS)and ferric antioxidant reducing power (FRAP) protocols were used for their radical scavenging and total antioxidant capacities respectively. Spontaneously hypertensive rats were used for acute antihypertensive study while for the 21 days antihypertensive study, hypertension was induced by administering L-Name (40 mg/kg) for 4 weeks and, CODA 8 Non-invasive tail cuff machine was used to measure blood pressure. With the aid of a semi-auto chemistry analyzer, lipid profile of Taraxacum officinale (TO) was determined using Biosinol reagents. TOL and TOR also significantly reduced systolic, diastolic and mean arterial blood pressures up until 4 hours with the leaf part most active in single dose study using SHR model. TOL and TOR also significantly lowered systolic, diastolic and mean arterial blood pressures with the leaf part most active in 21 days study using and L-Name-induced HTN models. However, these plant extracts did not have a diuretic effect, but seems to exert its antihypertensive effects by modulating NO production and possibly bioavailability, by acting via an endothelium-dependent pathway. This study validates the traditional use of the leaf part of the plant as an antihypertensive agent.

Made available in DSpace on 2014-06-11T19:31:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-08-13Bitstream added on 2014-06-13T20:21:48Z : No. of bitstreams: 1 freiriaoliveira_ah_dr_arafo.pdf: 2515742 bytes, checksum: 4422a86bb9655e970b69042b1ddd71bf (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / É de extrema importância para o funcionamento do organismo a manutenção da osmolaridade e volume dos líquidos corporais. O sistema nervoso central (SNC) tem um papel fundamental para esta manuntenção. O núcleo do trato solitário (NTS) é o sítio primário das aferências cardiovasculares e de osmorreceptores periféricos e se projeta à areas prosencefálicas envolvidas com a regulação cardiovascular e do equilíbrio hidroeletrolítico. Desta forma, o NTS pode fazer a ligação entre as aferências viscerais e o SNC e participar dos ajustes necessários a regulação da osmolaridade e da volemia. A maior porção dos neurônios do grupamento catelocaminérgicos A2 do bulbo está localizada na porção comissural no NTS (NTScom). Assim, os objetivos deste estudo foram: a) estudar os efeitos na pressão arterial, na ingestão de água e na excreção renal subsequentes a administração de NaCl 2 M, estímulo osmótico agudo, em ratos com lesão seletiva dos neurônios A2 do NTScom; b) estudar os efeitos na expressão da proteína c-FOS subsequente a administração de NaCl 2 M, em ratos com lesão seletiva dos neurônios A2 do NTScom, c) estudar alterações na expressão de RNAm no NTS após a administração de NaCl 2 M, d) estudar os efeitos na pressão arterial subsequentes a hemorragia hipotensiva, em ratos com lesão seletiva dos neurônios A2 do NTScom. Ratos Holtzman (280-320 g) ou ratos Sprague-Dawley (230-280 g) foram utilizados neste estudo. Para a lesão seletiva dos neurônios A2 do NTScom ou lesão fictícia (LF), os animais foram submetidos a uma craniotomia parcial e a superfície dorsal do bulbo foi exposta. A lesão seletiva dos neurônios noradredérgicos foi realizada por meio da injeção no... / The central nervous system has an important role controlling the mechanisms involved in the regulation of body fluid osmolality. The nucleus of the solitary tract (NTS) is the primary site of cardiovascular and peripheral osmoreceptors afferents and projects to prosencephalic areas involved in hydroelectrolytic balance and cardiovascular regulation. The great part of the catecholaminergic neurons of the A2 group is located in the commissural part of the NTS (NTScom). Thus, the aims of this study were: a) to verify the effects in the arterial pressure, water intake and renal excretion observed after intragastric (ig) 2 M NaCl in rats with lesion of the A2 neurons of the NTScom, b) to verify the effects in the c-Fos expression after ig 2 M NaCl in rats with lesion of the A2 neurons of the NTScom, c) to study changes in gene expression on NTS after ig 2 M NaCl, d) to study the effects in arterial pressure after hypotensive hemorrhage in rats with lesion of the A2 neurons of the NTScom.Male Holtzman rats (280-320 g) or Sprague-Dawley (250-280 g) were used. For the A2 lesion of the NTScom, a partial craniotomy of the occipital bone was performed, and the dorsal surface of the brainstem was exposed. The lesion was performed by the injection of the toxine anti-dopamine-β-hydroxylase-saporin into the NTScom to destroy A2 neurons in this region. Sham lesioned rats anti-IgG-saporin was injected into the NTScom. We observed that in A2 lesioned rats, ig 2 M NaCl induced a vasopressin dependent-pressor response, for at least 60 min. The water intake induced by sodium overload was also incremented in A2 lesioned rats, however the natriuresis and dieresis after 2 M NaCl were similar in both groups. After 2 M NaCl... (Complete abstract click electronic access below)

abstract: Background: Nearly 95% of Americans will develop hypertension, and 67% will not seek treatment. Furthermore, hypertension is the leading risk factor for coronary heart disease. While previous studies have increased the use of blood pressure medication among patients that have received hypertension education, medications may not work for everyone. Due to the life-threatening nature of this condition, it is essential to find an effective alternative for treatment. The purpose of this study was to examine the impact of organometallic complex supplementation on hypertension and left ventricular hypertrophy in 6-week old male Sprague-Dawley rats that were fed either standard rodent chow or a high fat diet for 10 weeks at a university in Arizona. Methods: Forty-two healthy six-week old male Sprague-Dawley rats were randomly assigned to one of three groups: plain water control, 0.6 mg/ml organometallic complex or 3.0 mg/ml organometallic complex as soon as they arrived. Each rat was then housed individually to prevent the sharing of microbiota through coprophagia. Rats in each treatment group were further divided into two dietary groups that were fed either a high fat diet containing 60% kcal fat that was changed every three days or standard rodent chow. Researchers were not blind to which rat was in each group. At the end of the 10-week study, rats were euthanized with an overdose of sodium pentobarbital (200 mg/kg, i.p.). Heart, left ventricle of the heart, liver, and spleen masses were recorded for each animal. Data were analyzed by two-way ANOVA using SigmaPlot 10.0 software. Results: At the conclusion of this study, the left ventricle mass of the rats in the high fat diet group were significantly larger than those in the chow group. Neither dose of the organometallic complex supplement prevented these effects induced by high fat feeding. Conclusion: The organometallic complex supplement was not effective at mitigating the effects of a high fat diet on cardiac hypertrophy in rats. Therefore, this supplement should not be used to treat cardiac hypertrophy. / Dissertation/Thesis / Masters Thesis Nutrition 2019

One in every 10 infants is born premature, with premature being defined as being born before 37 weeks gestation. The immediate concerns of premature birth are fairly well understood, but the long-term consequences are much less known. Previous studies have shown pulmonary insufficiencies in adulthood, but less have looked at hemodynamic variables. None have investigated exercise and hypoxia intolerance in adults who survived prematurity. The goals of this study were to determine exercise capacity and hemodynamic response during exercise and hypoxia in prematurely born adults, as well as deriving pulse wave velocity in normoxia and hypoxia. Preterm (N=10) and term-born, age-matched subjects (N=12) performed incremental exercise in normoxia (21% O2) or hypoxia (12% O2) until volitional maximum was reached. Subjects had arterial and venous catheters collecting blood gas concentration and blood pressure, and breath-by-breath metabolics gathering ventilation data. Preterm and term-born subjects were well matched for anthropometrics, pulmonary, and exercise capacity values. The preterm adults had elevated heart rates, systolic blood pressure, pulse pressure throughout the exercise protocol in normoxia and hypoxia. The preterm group experienced an increased diastolic blood pressure and mean arterial pressure during normoxic exercise, but had a transient decrease in diastolic blood pressure and mean arterial pressure in hypoxia. Additionally, adults born prematurely had an increase aortic pulse wave velocity (aPWV). With these findings, we aimed to determine if aortic stiffness was increased in premature infants at birth with the neonatal intensive care unit (NICU), or if there was a phenotype of premature aging in this population. Prior to beginning the study with the NICU, the effects of simulation on clinicians and researchers was investigated. Simulation is often used for noninvasive teaching or practicing procedures. No one has looked into the effect simulation has on research being done in an intensive care unit setting. Bay 1 and 2 nurses (n=23) in the NICU were surveyed to rate their thoughts of clinical research, comfort with new research, comfort with simulation, and comfort with researchers not from the NICU. Nurses did not know what aspects of the NICU were overwhelming to researchers nor did they agree that researchers could identify infants stress cue. Nurses also reported discomfort communicating with parents about novel research technology. But overall, nurses support research in the NICU and are comfortable with new research knowing the research team participated in a NICU-specific simulation. A questionnaire was also filled out by researchers (n=3), neonatal intensive care unit physicians (n=3) and nurses (n=3) prior to and after completing a research study simulation. Prior to simulation, scientists showed more unfamiliarity with the infants, the NICU setting, and simulation than did the physicians or nurses. Physicians and nurses, however, were not familiar with the technology the researchers used. The simulation alleviated the differences found among the groups. Simulation improves nurses’ opinions of new technology and researchers coming into the NICU and working with patients. Simulation helps researchers familiarize themselves with the NICU and infants, while also improving the clinicians’ comfort with the technology and methods being used.

Thesis (M Med (Family Medicine))--University of Limpopo, 2010. / Background: The state of Hypertension disease is universally under diagnosed and/or inadequately treated resulting in extensive target-organ damage and premature deaths. Therefore, sustainable and aggressive population-based programs for hypertension awareness, prevention, treatment, and control are keys of success in limiting this epidemic. The study aims to determine the Kang Adult population’s hypertension prevalence and the relationship between high blood pressure, anthropometric measures and their life style factors such as diet, use of tobacco products and alcohol consuming habits. Methodology: The study, a population based cross-sectional trial, was conducted on adult residents of Kang (18 year-old and above) from November to December 2008. Data was collected using the questionnaire, through physical measurements of weight, height and BP using a modified protocol based on World Health Organization (WHO) STEP wise instruments on chronic disease (Bonita, 2001). The sample consisted of 161 participants between 20 and 82 years of age. Results: Hypertension was observed in 31.6% of participants (95% CI: 24.6%-39.5%). With regard to the hypertension prevalence rate, no significant differences were observed between males and females (males 28.3% versus females 33.6%, p = 0.59). An elevated blood pressure was seen with significantly higher frequency in overweight group compared with the normal weight group (p = 0.029), in obese group compared x with the normal weight group (p = 0.002), and in obese group compared with the overweight group (p = 0.045). The study found no significant association between hypertension and use of tobacco products (p=0.46) or alcohol consumption (p=0.73), went in vigorous-intensity activity (p=0.22) and moderate-intensity activity that causes large increases in breathing, or heart rate for at least 10 minutes continuously (p=0.70). Conclusions: It is concluded that hypertension is a common problem in adult Kang population, with a prevalence of 31.6%. Hypertension prevalence was found to be associated with anthropometric measurements such as overweight and obesity. No significant association between hypertension and use of tobacco products, alcohol consumption, vigorous-intensity and moderate-intensity activities that cause increases in breathing or heart rate for at least 10 minutes continuously. However, the present study had the limitation of a small sample size. Further studies are needed to clarify the hypertension magnitude throughout the country, with large samples.

Models of steroid-induced hypertension in man and rat have been well characterized but the mechanisms by which ACTH and glucocorticoids raise blood pressure are not fully understood. Recently described paracrine (eg endothelial nitric oxide) and humoral (eg PHF) factors may be important in human essential hypertension. These factors were examined in cortisol-induced hypertension in man and ACTH-induced hypertension in the rat respectively. In man, the haemodynamic effects of ACTH can be attributed to the adrenal production of cortisol, but whether the major rodent glucocorticoid corticosterone is responsible for ACTH-induced hypertension in the rat has not been resolved. This question was examined in these studies. In male volunteers, exogenous cortisol raised blood pressure and suppressed endothelium-dependent vasodilatation, by a mechanism which may be nitric oxide synthase dependent. Although dexamethasone and fludrocortisone also raised blood pressure, attenuation of cholinergic vasodilatation was not observed. From these studies, the data suggest that the effect of cortisol on endothelium-dependent vasodilatation is unique to the endogenous hormone and not reproduced by synthetic agonists of GR or MR. Impaired endothelial vasodilator function may contribute to cortisol-induced hypertension in man. In the rat, exogenous corticosterone, administered in doses to achieve circulating concentrations similar to those observed in the experimental model of ACTH excess, reproduced the haemodynamic and some of the metabolic changes which characterize ACTH-induced hypertension. Further, like ACTH-induced hypertension, corticosterone-induced hypertension was prevented by L- but not D-arginine, and this effect was completely prevented by NOLA. It is likely that adrenal corticosterone mediates the hypertensive effects of ACTH excess. Parathyroidectomy had no significant effect on the rise in blood pressure secondary to ACTH excess. It is unlikely that PHF contributes to the model of ACTH-induced hypertension in the rat. The bioassay for the measurement of PHF could not be reproduced in our laboratory, leaving a question mark about the relevance of this putative factor in hypertension research.

Protein modification by ubiquitination regulates protein abundance, function and localisation. Specificity of ubiquitination is largely determined by ubiquitinprotein ligases (E3s). The Nedd4–family proteins are a group of E3s containing a conserved domain structure of a C2 domain, multiple WW domains and a carboxyl terminal HECT domain, which is responsible for E3 activity. The prototypical member of this family, Nedd4, is known to down-regulate the epithelial Na+ channel (ENaC) by ubiquitination. This process requires interactions between ENaC and specific WW domains of Nedd4. Mutation or deletion of WW domain binding sites in ENaC leads to Liddle's syndrome, an autosomal dominant form of hypertension. At the beginning of this study there was evidence to suggest that Nedd4–2, a Nedd4–family protein closely related to Nedd4, could also regulate ENaC. The focus of this study was to characterise the ability of Nedd4–2 to regulate ENaC and other potential substrates. Two major splice variants of Nedd4–2 were identified, which were both found to down–regulate ENaC in Xenopus oocytes. In vitro binding studies and whole cell functional analysis showed that interactions between ENaC and Nedd4– 2 occur via two of the four Nedd4–2 WW domains. The E3 activity of Nedd4–2 was further examined, revealing that it can use the same ubiquitin–conjugating enzymes as Nedd4 and exhibits strongest activity in the presence of UbcH5b. An in vitro ubiquitination assay and whole cell functional analysis provided evidence that Nedd4–2 down-regulates ENaC via ubiquitination. The possibility that Nedd4 and Nedd4–2 could down-regulate a number of voltage–gated Na+ channels (Navs) by a similar mechanism to regulation of ENaC was investigated. Not only were Nedd4 and Nedd4–2 found to interact with seven Navs, but these channels and ENaC have conserved WW domain binding specificity. Ubiquitination studies indicated that these channels can be ubiquitinated by Nedd4 and Nedd4–2. Co–expression of Nedd4 or Nedd4–2 with neuronal Navs in Xenopus oocytes reduced channel activity to varying degrees. These data indicate that Nedd4 and Nedd4–2 are likely to be key regulators of neuronal Nav channels in vivo. / Thesis (Ph.D.)--Department of Medicine, 2004.

The endothelial layer of blood vessels is able to produce a number of vasoactive substances, and these substances can work to either relax or contract the underlying vascular smooth muscle. A hallmark of hypertension is the development of endothelial dysfunction, a shift in the balance of these substances to a state of increased contraction. Hydrogen sulfide (H2S) has recently garnered much interest as a gaseous signaling molecule with the discoveries that is can relax isolated blood vessels and lower blood pressure in young spontaneously hypertensive rats (SHR). Here we investigate whether chronic H2S treatment (56 μmol/kg of the H2S donor sodium hydrosulfide (NaHS), once daily for 5 weeks) can lower the blood pressure of adult aged SHR when compared to normotensive control Wistar Kyoto rats (WKY), and whether there are changes in the endothelium-dependent relaxation and contraction pathways. Invasive hemodynamic measurements including systolic, diastolic, and mean blood pressure, as well as heart rate were measured. Isolated vessel myography was performed on the common carotid artery to determine whether there were changes in the endothelium-dependent and independent relaxation and contraction pathways. This was achieved using a number of dose response curves. Changes in endothelium dependent dilation to ACh, VSM sensitivity to NO and H2S, and NO bioavailability were tested with dose response curves using ACh, SNP (an NO donor), H2S and indomethacin, respectively. TP receptor sensitivity, as well as COX-mediated constriction in quiescent vessels was also examined by using the TP receptor agonist U46619 and L-NAME (eNOS inhibitor), respectively. Biochemical analyses included Western blotting to assess protein levels of CSE (H2S generating enzyme) and eNOS (NO generating enzyme) as well as determining prostacyclin production. Determination of H2S concentration in the blood via a sulfide electrode was also performed to confirm that the H2S treatment was effective. There were no main effects of H2S treatment in any of the hemodynamic measurements taken. ACh dose response revealed a blunting in the recontraction at 10-5 and 10-4.5 log M concentrations (p<0.05) in SHR treated with H2S. No effects were observed, however, in any other myography protocol. Western blot analysis revealed no difference in the protein expression of CSE or eNOS with H2S treatment, and there were no differences in prostacyclin production with H2S treatment. In conclusion, these data suggest that H2S may not be an effective treatment for hypertension in adult SHR, in contrast to previous work finding a similar dosing regimen to be effective at lowering blood pressure in young SHR. Further work must be completed to ascertain the mechanism for the alteration in the ACh dose response curve and to determine at what time point the H2S treatment becomes ineffective.