Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves [74-81]).

Thesis (M.S.)--Indiana University, 2003. / Includes bibliographical references. Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M.S.)--Indiana University, 2003. / Includes bibliographical references.

Hypertensive patients exhibit impaired exercise capacity, a strong independent risk factor for cardiovascular disease, and the mechanisms responsible for this are not fully determined. Potential candidates may include endothelial vasomotor dysfunction and arterial stiffness, both of which are associated with hypertension. Impairment of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a major role in the development of these abnormalities, suggesting that enhancement of NO-cGMP signalling through phosphodiesterase type 5 (PDE5) inhibition may offer therapeutic potential in arterial hypertension. This thesis investigated the effects of the PDE5 inhibitor sildenafil citrate on exercise-induced vasodilatation, maximal exercise capacity and arterial stiffness in hypertensive patients, using different studies involving local limb and whole body exercise. Preliminary dose-ranging studies were initially performed to investigate the intraarterial (brachial) effects of sildenafil on forearm blood flow (FBF), and to select an appropriate, cGMP-independent, vasodilator to use as a control. On the basis on these studies, it was established that sildenafil, infused at 50μg/min, and verapamil, infused at 5μg/min, had similar vasodilator effect on FBF. Ten untreated hypertensive patients and ten matched normotensive subjects were then studied in a three-way, randomised, single-blind and placebo-controlled FBF study. The aim was to investigate the effects of sildenafil on handgrip exercise-induced vasodilatation, and to compare this response with verapamil and saline (placebo). Preinfusion exercise-induced vasodilatation was significantly reduced in hypertensive compared with normotensive subjects (P<0.001). However, after the infusions, while verapamil did not affect the vasodilator response to exercise in either group, sildenafil substantially enhanced this response in hypertensive patients, but not in normotensive subjects (P<0.05). These results suggested that sildenafil, through an increase in cGMP levels in the vasculature, substantially and selectively improves the vasodilator response to handgrip exercise in hypertensive patients.

A hipertensão arterial (HA) é uma síndrome multifatorial caracterizada por níveis elevados e sustentados de pressão arterial (PA). O treinamento físico (TF) aeróbio tem sido utilizado como um importante tratamento não farmacológico da HA, uma vez que ele corrige a rarefação microvascular e o perfil de fibras muscular e reduz a PA; entretanto, os mecanismos envolvidos são pouco conhecidos. Uma nova classe de pequenos RNAs, denominados de microRNAs (miRNAs), vem sendo muito estudados por regularem pós-transcricionalmente a expressão de seus genes alvo. Estudos avaliando o papel dos miRNAs na regulação do processo angiogênico e trofismo muscular tanto na HA quanto induzidos pelo TF são desconhecidos. Portanto, nosso objetivo é caracterizar o perfil de miRNAs e genes alvo do músculo esquelético envolvidos nos processos de rarefação microvascular e dano muscular na HA e verificar o papel terapêutico do TF de natação na correção desses parâmetros. Na primeira etapa do projeto, ratos espontaneamente hipertensos (SHR) com 3 meses de idade (HA recém estabelecida) e seus controles Wistar Kyoto (WKY) foram divididos em 4 grupos: SHR, SHR treinado (SHR-T), WKY e WKY treinando (WKY-T). O TF promoveu redução da PA em SHR e bradicardia de repouso acompanhando por um aumento VO2 nos animais treinados. O TF corrigiu a mudança na distribuição dos tipos de fibra muscular em SHR paralelamente a correção na expressão do miRNA-208b. A rarefação capilar foi prevenida em animais SHR-T concomitante a correção na expressão dos miRNAs-16, -21 e -126 envolvidos na promoção das vias angiogênicas e desativação de vias apoptóticas por alvejarem VEGF, Bcl-2 e PI3KR2. Na segunda etapa do projeto, SHR com 6 meses de idade (HA crônica) e seus controles WKY foram divididos nos mesmos 4 grupos da primeira etapa. Similares resultados foram observados nas respostas hemodinâmicas, mudança no perfil de fibras muscular e rarefação capilar. Em contraste, foi observado uma redução do VO2 acompanhado por uma atrofia e disfunção muscular em SHR. Além disso, estes animais apresentavam disfunção cardíaca e aumento na relação parede-lúmen da artéria femoral e arteríola muscular. O TF corrigiu estas alterações no vaso e no músculo. Curiosamente, o microarray de miRNAs muscular revelou um perfil de miRNAs envolvidos no remodelamento microvascular e muscular esquelético (miRNAs-96, -205, -182, -140, -328a, -665, -1, -499, -208b e -99b) possibilitando identificar genes alvo modificados pela HA e TF. Assim, alvos envolvidos na mudança do perfil de fibras, síntese protéica via IGF-I/ Akt/ mTOR e da via de sinalização angiogênica dependente e independente de VEGF foram prejudicadas na HA e corrigidos pelo TF. Juntos, os resultados apoiam a hipótese de que as alterações estruturais e funcionais advindas da progressão da HA possa ser regulada por um conjunto de miRNAs e genes alvo; e que o TF participa no restabelecimento muscular e da rede microvascular. Assim, há perspectiva do potencial terapêutico do uso de miRNAs no tratamento da HA / Hypertension is a multifactorial syndrome characterized by sustained high levels of blood pressure (BP). Aerobic exercise training (ET) has been used as an important non-pharmacological treatment of hypertension, since it corrects microvascular rarefaction, muscle fiber type profile and reduces BP; however, the mechanisms involved are poorly understood. A new class of small RNAs, called microRNAs (miRNAs), has been extensively studied because they regulate their target gene expression at the post-transcriptional level. Studies evaluating the role of miRNAs in the angiogenic process and muscle trophism both in hypertension and exercise training are unknown. Therefore, our goal is to characterize the skeletal muscle miRNA profiles and their target genes involved in microvascular rarefaction and muscle damage in hypertension and check the therapeutic role of swimming ET in correcting these parameters. In the first stage of the project, spontaneously hypertensive rats (SHR) aged 3 months (hypertension newly established) and their controls Wistar Kyoto (WKY) were divided into 4 groups: SHR, trained SHR (SHR-T), WKY and WKY training (WKY-T). ET promoted reduction in BP in SHR and resting bradycardia with subsequent increase in VO2in trained animals. ET corrected the change in proportion of muscle fiber types in SHR parallel with the correction in miRNA-208b expression. Capillary rarefaction was prevented in SHR-T group concomitant with the correction in the expression of miRNAs-16, -21 and -126 involved in promoting angiogenesis and deactivation of apoptotic pathways by targeting VEGF, Bcl-2 and PI3KR2. In the second stage of the project, 6-month-old SHR (chronic hypertension) and their controls WKY were divided into the same four groups as those in the first stage. Similar results were observed in hemodynamic responses, muscle fiber profile and capillary rarefaction. In contrast, we observed a reduction in VO2 accompanied by muscle atrophy and dysfunction in SHR. Moreover, these animals showed cardiac dysfunction and an increase in wall:lumen ratio of the femoral artery and muscle arteriole. ET corrected these changes in the vessel and muscle. Interestingly, the muscle miRNA microarray revealed a profile of miRNAs involved in microvascular and muscle remodeling (miRNAs-96, -205, -182, -140, - 328a, -665, -1, -499, -208b and -99b) making it possible to identify target genes modified by hypertension and ET. Thus, targets involved in changing the fiber profile, protein synthesis by the IGF-I/ Akt /mTOR pathway, and the VEGF-dependent and independent angiogenic signaling pathway, were impaired in hypertension and corrected by ET. Together, these results support the hypothesis that the structural and functional changes arising from the progression of hypertension may be regulated by a set of miRNAs and target genes; and ET participates in restoring the muscle and microvascular network. Thus, there are perspectives for the potential therapeutic use of miRNAs in the treatment of hypertension

A hipertensão arterial (HA) é uma síndrome multifatorial caracterizada por níveis elevados e sustentados de pressão arterial (PA). O treinamento físico (TF) aeróbio tem sido utilizado como um importante tratamento não farmacológico da HA, uma vez que ele corrige a rarefação microvascular e o perfil de fibras muscular e reduz a PA; entretanto, os mecanismos envolvidos são pouco conhecidos. Uma nova classe de pequenos RNAs, denominados de microRNAs (miRNAs), vem sendo muito estudados por regularem pós-transcricionalmente a expressão de seus genes alvo. Estudos avaliando o papel dos miRNAs na regulação do processo angiogênico e trofismo muscular tanto na HA quanto induzidos pelo TF são desconhecidos. Portanto, nosso objetivo é caracterizar o perfil de miRNAs e genes alvo do músculo esquelético envolvidos nos processos de rarefação microvascular e dano muscular na HA e verificar o papel terapêutico do TF de natação na correção desses parâmetros. Na primeira etapa do projeto, ratos espontaneamente hipertensos (SHR) com 3 meses de idade (HA recém estabelecida) e seus controles Wistar Kyoto (WKY) foram divididos em 4 grupos: SHR, SHR treinado (SHR-T), WKY e WKY treinando (WKY-T). O TF promoveu redução da PA em SHR e bradicardia de repouso acompanhando por um aumento VO2 nos animais treinados. O TF corrigiu a mudança na distribuição dos tipos de fibra muscular em SHR paralelamente a correção na expressão do miRNA-208b. A rarefação capilar foi prevenida em animais SHR-T concomitante a correção na expressão dos miRNAs-16, -21 e -126 envolvidos na promoção das vias angiogênicas e desativação de vias apoptóticas por alvejarem VEGF, Bcl-2 e PI3KR2. Na segunda etapa do projeto, SHR com 6 meses de idade (HA crônica) e seus controles WKY foram divididos nos mesmos 4 grupos da primeira etapa. Similares resultados foram observados nas respostas hemodinâmicas, mudança no perfil de fibras muscular e rarefação capilar. Em contraste, foi observado uma redução do VO2 acompanhado por uma atrofia e disfunção muscular em SHR. Além disso, estes animais apresentavam disfunção cardíaca e aumento na relação parede-lúmen da artéria femoral e arteríola muscular. O TF corrigiu estas alterações no vaso e no músculo. Curiosamente, o microarray de miRNAs muscular revelou um perfil de miRNAs envolvidos no remodelamento microvascular e muscular esquelético (miRNAs-96, -205, -182, -140, -328a, -665, -1, -499, -208b e -99b) possibilitando identificar genes alvo modificados pela HA e TF. Assim, alvos envolvidos na mudança do perfil de fibras, síntese protéica via IGF-I/ Akt/ mTOR e da via de sinalização angiogênica dependente e independente de VEGF foram prejudicadas na HA e corrigidos pelo TF. Juntos, os resultados apoiam a hipótese de que as alterações estruturais e funcionais advindas da progressão da HA possa ser regulada por um conjunto de miRNAs e genes alvo; e que o TF participa no restabelecimento muscular e da rede microvascular. Assim, há perspectiva do potencial terapêutico do uso de miRNAs no tratamento da HA / Hypertension is a multifactorial syndrome characterized by sustained high levels of blood pressure (BP). Aerobic exercise training (ET) has been used as an important non-pharmacological treatment of hypertension, since it corrects microvascular rarefaction, muscle fiber type profile and reduces BP; however, the mechanisms involved are poorly understood. A new class of small RNAs, called microRNAs (miRNAs), has been extensively studied because they regulate their target gene expression at the post-transcriptional level. Studies evaluating the role of miRNAs in the angiogenic process and muscle trophism both in hypertension and exercise training are unknown. Therefore, our goal is to characterize the skeletal muscle miRNA profiles and their target genes involved in microvascular rarefaction and muscle damage in hypertension and check the therapeutic role of swimming ET in correcting these parameters. In the first stage of the project, spontaneously hypertensive rats (SHR) aged 3 months (hypertension newly established) and their controls Wistar Kyoto (WKY) were divided into 4 groups: SHR, trained SHR (SHR-T), WKY and WKY training (WKY-T). ET promoted reduction in BP in SHR and resting bradycardia with subsequent increase in VO2in trained animals. ET corrected the change in proportion of muscle fiber types in SHR parallel with the correction in miRNA-208b expression. Capillary rarefaction was prevented in SHR-T group concomitant with the correction in the expression of miRNAs-16, -21 and -126 involved in promoting angiogenesis and deactivation of apoptotic pathways by targeting VEGF, Bcl-2 and PI3KR2. In the second stage of the project, 6-month-old SHR (chronic hypertension) and their controls WKY were divided into the same four groups as those in the first stage. Similar results were observed in hemodynamic responses, muscle fiber profile and capillary rarefaction. In contrast, we observed a reduction in VO2 accompanied by muscle atrophy and dysfunction in SHR. Moreover, these animals showed cardiac dysfunction and an increase in wall:lumen ratio of the femoral artery and muscle arteriole. ET corrected these changes in the vessel and muscle. Interestingly, the muscle miRNA microarray revealed a profile of miRNAs involved in microvascular and muscle remodeling (miRNAs-96, -205, -182, -140, - 328a, -665, -1, -499, -208b and -99b) making it possible to identify target genes modified by hypertension and ET. Thus, targets involved in changing the fiber profile, protein synthesis by the IGF-I/ Akt /mTOR pathway, and the VEGF-dependent and independent angiogenic signaling pathway, were impaired in hypertension and corrected by ET. Together, these results support the hypothesis that the structural and functional changes arising from the progression of hypertension may be regulated by a set of miRNAs and target genes; and ET participates in restoring the muscle and microvascular network. Thus, there are perspectives for the potential therapeutic use of miRNAs in the treatment of hypertension

M.A. (Psychology) / Against the background of increasing costs of treatment of hypertension amongst the South African Black population, a non-pharmacological treatment model in the form of relaxation and aerobic fitness training was developed. The relaxation and aerobic fitness training model was then evaluated in a pretest-post test experimental and control group design. The findings indicated that the relaxation training as well as the aerobic fitness training showed statistical and clinical significant decreases in both systolic and diastolic blood pressure levels...

Ischemic heart disease and resulting heart failure (HF) belong to the leading causes of death in developed countries. In order to prevent HF and improve clinical outcome in patients with myocardial infarction, novel therapies are required to protect the heart against the detrimental effect of ischemic injury. Due to the failure to translate numerous available experimental cardioprotective strategies into clinical practice, the need for novel protective treatments persists. We have, therefore, tried to apply a novel approach to cardiac protection against the postischemic HF induced in rats by ligation of the coronary artery. For this purpose, we have studied (i) the preventive and therapeutic effects of adaptation to continuous normobaric hypoxia (CNH; 12% O2) and exercise training (ExT; treadmill running), and (ii) the possible cardioprotective potential of epoxyeicosatrienoic acid (EET)-based therapy in order to attenuate the postischemic HF in rats. Adaptation to CNH and ExT is known for their cardioprotection in acute ischemia/reperfusion (I/R) injury manifested as reduction of infarct size. EETs exert antihypertensive effects and thus seem to be perspective for the research in clinically relevant models of cardioprotection in hypertensive animals. Our results have revealed that: - CNH prior to...

D.Litt. et Phil. / A problematic aspect of the latter half of the twentieth century in the South African health context, has been the change of the incidence of hypertension amongst black South Africans from being barely. endemic to being a virtual epidemic. This change in hypertension has had several negative components, notably the development of malignant hypertension wherein a markedly accelerated rate of development in hypertension has led to severely high incidences of morbidity and mortality amongst black South Africans notably in urban areas. Many researchers have cited the rapid process of urbaniztion as being the major cause, of this rapid rise in the relative incidence of hypertension amongst black South Africans. Whereas previously, the rapid rise of hypertension in urbanizing black South Africans has been attributed to the social readjustment, associated with urbanization, recent research have suggested that it is not only stressrelated, but also related to a change in basic lifestyle. Basic lifestyle changes have been found to include a change in work ethic from being a rural, cooperative work ethic, to being an urbanized firstworld type A, aggressive, competitive workstyle. This has led also to changes in eating habits with the ingestion of more salt, fats and oils, and has led to a hurried, but non exercised lifestyle. Because of the rapid increase of incidence of hypertension amongst black South Africans, the treatment of this condition has become problematic~ While black South Africans do not respond as well to traditional pharmacological interventions in this condition, they also show side-effects which make it very difficult for them to continue taking this medication. The cost aspects have also been noted to be prohibitively high and the availability of medicines because of the cost aspects has been projected to decline in the coming century. For this reason it would be "important to address other adjunctive measures to treat hypertension amongst black South Africans. In addition to standard harmacological interventions , it appears that there has been mention in the Iiterature of. lifestyle changes to be an efficacious intervention method in stabilizing and reducing blood pressure amongst hypertensives. This has however not been investigated individually or systematically amongst black South Africans. It was therefore the purpose of this study to investigate the effectiveness of lifestyle intervention programs, notably an aerobic exercise intervention, a dietary intervention, and an intervention to increase assertiveness and therefore reduce the aggressiveness associated with the competitive working style acquired by black South Africans. In order to test the efficacy of these treatment measures, a large group of black mineworkers were selected on a basis of meeting the diagnostic criteria for essential hypertension. These black mineworkers were then systematically sUbjected to an aerobic exercise intervention, a dietary intervention, and anger management by means of assertiveness training. Various measures were performed on a pretest and posttest basis. All three interventions were shown to have moderate efficacy. It was found that aerobic exercise, the dietary intervention and the anger management to be associated with a decline in both systolic and diastolic blood pressure, and to be associated with a reduction in the taking of hypertensive medication as ordered by the attending physicians. The aerobic exercise intervention also indicated that black South African mineworkers are relatively unfit and a ch~nge in fitness resulted in a decline in systolic and diastolic blood pressure. The dietary intervention proved to be efficient in terms of changing lifestyle eating habits. Of note is the fact that there was a substantial decrease in the taking of medication when compared to a· control group. It would appear from this research that the specific forms of lifestyle change in black hypertensives noted in this study would be an efficient adjunct or even a substitute for present treatment of hypertension amongst black mineworkers.