Motivation: Abdominal obesity (hereafter referred to as "obesity") is becoming the biggest "global epidemic" of our modern times. It is associated with a range of diseases, including cardiovascular diseases and hypertension. Recent research showed that an increase in sympathetic activity is of central importance in the pathogenesis of obesity-related diseases. Increased leptin levels and impaired baroreflex sensitivity have both been independently associated with abdominal obesity and increased sympathetic activity. A perception of poorer health may also contribute to the physiological characteristics of obesity-related diseases. A lack of data regarding sympathetic activity, leptin levels, baroreflex sensitivity and perception of health in Africans, serves as a motivation for conducting this study. Objective: To investigate the contributions of leptin levels, baroreflex sensitivity and perception of health data to increased sympathetic activity in lean and obese African women from South Africa. Methodology: The manuscript presented in Chapter 2 made use of the data obtained in the POWIRS (Profiles of Obese Women with the Insulin Resistance Syndrome) study. A group of 102 urbanized African women, living in the North-West Province of South Africa, was recruited according to body mass indexes. Only 85 subjects were included for analysis due to incomplete datasets. For this study, subjects were divided into lean and obese groups according to their waist circumferences. Anthropometric measurements were done according to standardized methods. Resting cardiovascular measurements were obtained from Finometer observations. Resting, fasting levels of leptin were calculated after radioimmunoassay analyses. Subjective perception of health was determined by means of the 28-item General Health Questionnaire. Comparisons between the groups were done using analysis of covariance (ANCOVA) whilst adjusting for cardiovascular risk factors (age. smoking, alcohol consumption and physical activity). Correlation coefficients were determined to indicate any associations between leptin, baroreflex sensitivity and perception of health with sympathetic activity (represented by heart rate) and other cardiovascular variables. The study was approved by the Ethics committee of the North-West University and all the subjects gave informed consent in writing. The reader is referred to the Methods section in Chapter 2 for a more detailed description of the subjects, study design and analytical procedures used in this dissertation. Results and conclusion: Results from this study indicate that obese African women, compared to lean African women, were older, reported higher physical activity, and exhibited higher diastolic and mean blood pressure, heart rate, cardiac output, arterial compliance, leptin and hypertension prevalence rate values. In lean African women social dysfunction was positively associated with diastolic and mean blood pressure and arterial resistance, and negatively with arterial compliance. In obese African women baroreflex sensitivity was negatively associated with diastolic blood pressure, which could be an indication of impaired baroreflex sensitivity. In this obese group a perception of social dysfunction was associated with decreased heart rate. Although leptin and heart rate were significantly higher in the obese Africans, no significant correlations existed between these variables to reflect leptin's enhancement of sympathetic activity. However, leptin correlated weakly but positively with cardiac output (p = 0.054, r = 0.32). In conclusion, baroreflex sensitivity (although similar between groups) and leptin seem to contribute to blood pressure and thus hypertension in obese African women, possibly through increased sympathetic activity and volume loading. A perception of poorer health, especially a perception of social dysfunction, could possibly contribute to this image. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2007.

A privação do sono é um problema sério nos tempos atuais e pode ter graves conseqüências para a fisiologia humana. De fato, a redução no tempo de sono tem sido associada a um notável aumento na incidência de hipertensão arterial, diabetes mellitus, infarto do miocárdio, acidente vascular cerebral e estresse, porém os mecanismos envolvidos são pobremente compreendidos. Objetivos: Avaliar o impacto da privação parcial do sono na função endotelial venosa e no controle autonômico cardiovascular em homens saudáveis. Métodos: Treze voluntários do sexo masculino, saudáveis e com idade média de 31±2 anos, tiveram o sono monitorado por diário de sono e actigrafia de pulso durante 12 noites consecutivas, nas quais foram divididas em 2 dois períodos. Um período de 5 noites denominado de privação parcial do sono (dormir<5h por noite) e outro de 5 noites denominado de sono controle (dormir>7h por noite). Entre estes períodos, foi interposto por 2 noites de sono irrestrito (com pelo menos de 7 horas de sono por noite). A escolha do período inicial de sono foi randomizada. Ao término de cada período de 5 dias, foi analisada a reatividade vascular venosa (com a técnica da veia do dorso da mão, Dorsal Hand Vein), a sonolência diurna excessiva (através da Escala de Sonolência de Epworth), realizada avaliação hemodinâmica e autonômica (no momento em repouso e mediante o teste de inclinação postural tilt test), exames de sangue e dosagem de norepinefrina plasmática. A freqüência cardíaca e pressão arterial de batimento a batimento na posição supina e com a manobra de \"tilt test\" foi monitorado com intervalo (RR) e variabilidade de pressão arterial. Resultados: Os indivíduos dormiram em média 8.0 h durante o período de sono controle e 4.5 h no período de privação parcial do sono, sendo a diferença significativa entre os mesmos (p<0.01). O período privação de sono não mudou a frequência cardíaca e a pressão arterial basal significativamente, mas promoveu um aumento significante em baixas freqüências cardíacas e variabilidade da pressão arterial, como também na norepinefrina plasmática. O \"tilt test\" promoveu uma queda em PA sistólica depois da privação parcial do sono, que foi significativamente maior depois do período de sono controle (p<0.05). A privação parcial do sono causou uma redução significantiva na venodilatação endotélio-dependente e não mudou venodilatação endotélio-independente. Conclusão: Privação parcial do sono durante só 5 noites já é o suficiente para causar disfunção endotelial venosa, um aumento significantivo na atividade simpática e no prejuízo do controle da pressão arterial / Background: Sleep curtailment is a serious and common problem in western societies and can have significant consequences in the human physiology. In fact epidemiological studies showed that sleep deprivation (reduction in sleeping time) is associated with increased blood pressure, higher incidence of diabetes mellitus, myocardial heart attack, strokes in the brain, and stress, however the mechanisms are poorly understood. Objectives: Evaluate the impact of partial sleep deprivation in the venous endothelial function and the autonomic cardiovascular autonomic control in healthy men. Methods: Thirteen healthy male volunteers (average age: 31±2 years) had their sleep monitored by sleep diary and wrist actigraphy during 12 consecutive nights, these were divided into two periods. The subjects were randomized and crossed over to 5 nights of control sleep (> 7hs) and 5 nights of partial sleep deprivation (<5hs), interposed by 2 nights of unrestricted sleep (at least 7 hours sleep per night). The choice of the initial sleeping period was randomized. At the end of each period of 5 days heart rate and beat-to-beat blood pressure in the supine position and head up tilt test maneuver were monitored with off line determination of RR-interval and blood pressure variability. In addition, serum norepinephrine and venous endothelial functions were measured by dorsal hand vein technique; also we performed the evaluation of excessive day sleepiness (evaluated through the Epworth Sleepiness Scale), hemodynamic and autonomous evaluation (during sleep and through the tilt test). Results: The subjects slept 8.0 and 4.5 hs during control and partial sleep deprivation periods, respectively (p<0.01). Sleep deprivation did not change significantly the resting heart rate and blood pressure but promoted a significant increase in the low frequency bands of heart rate and blood pressure variability as well as serum norepinephrine. Tilt test promoted a significantly greater drop in systolic BP after partial sleep deprivation than after control sleep (p<0.05). Partial sleep deprivation caused a considerable reduction of acetylcholine induced venodilatation (endothelium dependent) and did not change sodium nitroprusside venodilatation (independent from the endothelium). Conclusion: Partial sleep deprivation for only 5 nights is sufficient to cause significant increase in sympathetic activity, impairment of blood pressure control and endothelial dysfunction

A privação do sono é um problema sério nos tempos atuais e pode ter graves conseqüências para a fisiologia humana. De fato, a redução no tempo de sono tem sido associada a um notável aumento na incidência de hipertensão arterial, diabetes mellitus, infarto do miocárdio, acidente vascular cerebral e estresse, porém os mecanismos envolvidos são pobremente compreendidos. Objetivos: Avaliar o impacto da privação parcial do sono na função endotelial venosa e no controle autonômico cardiovascular em homens saudáveis. Métodos: Treze voluntários do sexo masculino, saudáveis e com idade média de 31±2 anos, tiveram o sono monitorado por diário de sono e actigrafia de pulso durante 12 noites consecutivas, nas quais foram divididas em 2 dois períodos. Um período de 5 noites denominado de privação parcial do sono (dormir<5h por noite) e outro de 5 noites denominado de sono controle (dormir>7h por noite). Entre estes períodos, foi interposto por 2 noites de sono irrestrito (com pelo menos de 7 horas de sono por noite). A escolha do período inicial de sono foi randomizada. Ao término de cada período de 5 dias, foi analisada a reatividade vascular venosa (com a técnica da veia do dorso da mão, Dorsal Hand Vein), a sonolência diurna excessiva (através da Escala de Sonolência de Epworth), realizada avaliação hemodinâmica e autonômica (no momento em repouso e mediante o teste de inclinação postural tilt test), exames de sangue e dosagem de norepinefrina plasmática. A freqüência cardíaca e pressão arterial de batimento a batimento na posição supina e com a manobra de \"tilt test\" foi monitorado com intervalo (RR) e variabilidade de pressão arterial. Resultados: Os indivíduos dormiram em média 8.0 h durante o período de sono controle e 4.5 h no período de privação parcial do sono, sendo a diferença significativa entre os mesmos (p<0.01). O período privação de sono não mudou a frequência cardíaca e a pressão arterial basal significativamente, mas promoveu um aumento significante em baixas freqüências cardíacas e variabilidade da pressão arterial, como também na norepinefrina plasmática. O \"tilt test\" promoveu uma queda em PA sistólica depois da privação parcial do sono, que foi significativamente maior depois do período de sono controle (p<0.05). A privação parcial do sono causou uma redução significantiva na venodilatação endotélio-dependente e não mudou venodilatação endotélio-independente. Conclusão: Privação parcial do sono durante só 5 noites já é o suficiente para causar disfunção endotelial venosa, um aumento significantivo na atividade simpática e no prejuízo do controle da pressão arterial / Background: Sleep curtailment is a serious and common problem in western societies and can have significant consequences in the human physiology. In fact epidemiological studies showed that sleep deprivation (reduction in sleeping time) is associated with increased blood pressure, higher incidence of diabetes mellitus, myocardial heart attack, strokes in the brain, and stress, however the mechanisms are poorly understood. Objectives: Evaluate the impact of partial sleep deprivation in the venous endothelial function and the autonomic cardiovascular autonomic control in healthy men. Methods: Thirteen healthy male volunteers (average age: 31±2 years) had their sleep monitored by sleep diary and wrist actigraphy during 12 consecutive nights, these were divided into two periods. The subjects were randomized and crossed over to 5 nights of control sleep (> 7hs) and 5 nights of partial sleep deprivation (<5hs), interposed by 2 nights of unrestricted sleep (at least 7 hours sleep per night). The choice of the initial sleeping period was randomized. At the end of each period of 5 days heart rate and beat-to-beat blood pressure in the supine position and head up tilt test maneuver were monitored with off line determination of RR-interval and blood pressure variability. In addition, serum norepinephrine and venous endothelial functions were measured by dorsal hand vein technique; also we performed the evaluation of excessive day sleepiness (evaluated through the Epworth Sleepiness Scale), hemodynamic and autonomous evaluation (during sleep and through the tilt test). Results: The subjects slept 8.0 and 4.5 hs during control and partial sleep deprivation periods, respectively (p<0.01). Sleep deprivation did not change significantly the resting heart rate and blood pressure but promoted a significant increase in the low frequency bands of heart rate and blood pressure variability as well as serum norepinephrine. Tilt test promoted a significantly greater drop in systolic BP after partial sleep deprivation than after control sleep (p<0.05). Partial sleep deprivation caused a considerable reduction of acetylcholine induced venodilatation (endothelium dependent) and did not change sodium nitroprusside venodilatation (independent from the endothelium). Conclusion: Partial sleep deprivation for only 5 nights is sufficient to cause significant increase in sympathetic activity, impairment of blood pressure control and endothelial dysfunction

Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2007.

Motivation: Abdominal obesity (hereafter referred to as "obesity") is becoming the biggest "global epidemic" of our modern times. It is associated with a range of diseases, including cardiovascular diseases and hypertension. Recent research showed that an increase in sympathetic activity is of central importance in the pathogenesis of obesity-related diseases. Increased leptin levels and impaired baroreflex sensitivity have both been independently associated with abdominal obesity and increased sympathetic activity. A perception of poorer health may also contribute to the physiological characteristics of obesity-related diseases. A lack of data regarding sympathetic activity, leptin levels, baroreflex sensitivity and perception of health in Africans, serves as a motivation for conducting this study. Objective: To investigate the contributions of leptin levels, baroreflex sensitivity and perception of health data to increased sympathetic activity in lean and obese African women from South Africa. Methodology: The manuscript presented in Chapter 2 made use of the data obtained in the POWIRS (Profiles of Obese Women with the Insulin Resistance Syndrome) study. A group of 102 urbanized African women, living in the North-West Province of South Africa, was recruited according to body mass indexes. Only 85 subjects were included for analysis due to incomplete datasets. For this study, subjects were divided into lean and obese groups according to their waist circumferences. Anthropometric measurements were done according to standardized methods. Resting cardiovascular measurements were obtained from Finometer observations. Resting, fasting levels of leptin were calculated after radioimmunoassay analyses. Subjective perception of health was determined by means of the 28-item General Health Questionnaire. Comparisons between the groups were done using analysis of covariance (ANCOVA) whilst adjusting for cardiovascular risk factors (age. smoking, alcohol consumption and physical activity). Correlation coefficients were determined to indicate any associations between leptin, baroreflex sensitivity and perception of health with sympathetic activity (represented by heart rate) and other cardiovascular variables. The study was approved by the Ethics committee of the North-West University and all the subjects gave informed consent in writing. The reader is referred to the Methods section in Chapter 2 for a more detailed description of the subjects, study design and analytical procedures used in this dissertation. Results and conclusion: Results from this study indicate that obese African women, compared to lean African women, were older, reported higher physical activity, and exhibited higher diastolic and mean blood pressure, heart rate, cardiac output, arterial compliance, leptin and hypertension prevalence rate values. In lean African women social dysfunction was positively associated with diastolic and mean blood pressure and arterial resistance, and negatively with arterial compliance. In obese African women baroreflex sensitivity was negatively associated with diastolic blood pressure, which could be an indication of impaired baroreflex sensitivity. In this obese group a perception of social dysfunction was associated with decreased heart rate. Although leptin and heart rate were significantly higher in the obese Africans, no significant correlations existed between these variables to reflect leptin's enhancement of sympathetic activity. However, leptin correlated weakly but positively with cardiac output (p = 0.054, r = 0.32). In conclusion, baroreflex sensitivity (although similar between groups) and leptin seem to contribute to blood pressure and thus hypertension in obese African women, possibly through increased sympathetic activity and volume loading. A perception of poorer health, especially a perception of social dysfunction, could possibly contribute to this image. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2007.

Central mechanisms involving aldosterone - mineralocorticoid receptor (MR) activation mediate the increase in sympathetic tone after myocardial infarction (MI). We hypothesized that an increase in cardiac sympathetic activity (CSA) post MI facilitates cardiac sympathetic axonal sprouting, and that central MR blockade attenuates CSA and reduces cardiac sympathetic hyperinnervation post MI. Western blotting and qRT-PCR were used to assess protein and gene expression, and fluorescent immunohistochemistry was used to study changes in sympathetic innervation. Tyrosine hydroxylase (TH) and Norepinephrine transporter protein content in the non-infarcted base of the heart remained unaltered. In contrast, protein gene product (PGP 9.5) protein was significantly increased 2 fold in the base of the heart, and 6 fold in the peri-infarct area at 1 wk post MI, and associated with increased ubiquitin expression. Cardiac myocytes rather than sympathetic axons were identified as the main source of elevated PGP 9.5 expression. At the infarct border sympathetic hyperinnervation was observed with a 4 fold increase in growth associated protein 43 (GAP 43), a 2 fold increase in TH and a 50% increase in PGP 9.5 positive fibers when compared to the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone at 5 ug/day for 9 days post MI markedly attenuated the increase in TH, GAP 43 and PGP 9.5 nerve densities at the infarct border. Central MR blockade may attenuate sympathetic hyperinnervation by several mechanisms, including decreasing CSA post MI, or affecting expression or function of nerve growth factor protein. Marked PGP 9.5 expression occurs in cardiomyocytes early post MI, which may contribute to the increase in ubiquitin and the early cardiac remodeling post MI.

Submitted by Livia Mello (liviacmello@yahoo.com.br) on 2016-10-14T13:19:28Z No. of bitstreams: 1 TeseEVL.pdf: 11027777 bytes, checksum: 41dbb4fdedb476e263115ce57e0a47fd (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-11-08T18:47:31Z (GMT) No. of bitstreams: 1 TeseEVL.pdf: 11027777 bytes, checksum: 41dbb4fdedb476e263115ce57e0a47fd (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-11-08T18:47:43Z (GMT) No. of bitstreams: 1 TeseEVL.pdf: 11027777 bytes, checksum: 41dbb4fdedb476e263115ce57e0a47fd (MD5) / Made available in DSpace on 2016-11-08T18:47:52Z (GMT). No. of bitstreams: 1 TeseEVL.pdf: 11027777 bytes, checksum: 41dbb4fdedb476e263115ce57e0a47fd (MD5) Previous issue date: 2016-08-05 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / The exposure to periods of hypoxemia and reoxygenation, as observed in patients with obstructive sleep apnea (OSA), promotes compensatory increases in ventilation, sympathetic activity and blood pressure (BP), by mechanisms not fully understood. In the present study, we investigated the central mechanisms responsible for the cardiorespiratory changes induced by acute intermittent hypoxia (AIH; 10 episodes of 6-7% O2 for 45 sec, every 5 min hyperoxia) either in adult male rats (270-280 g) anesthetized with urethane (1.2 g / kg, ip) or in in situ working heart-brainstem preparations of juvenile male rats (65-75 g). In in situ preparations, the AIH promoted long-term facilitation (LTF), of at least 1 hour, in the phrenic nerve (PN), abdominal (AbN) and thoracic sympathetic (tSN) activities (n=9, P<0.05). In these animals, we observed that the increase in tSN activity induced by AIH occurred during the late part of expiratory period, namely late-expiratory (late-E) phase, coupled with the emergence of late-E bursts in AbN activity. Considering studies showing the role of serotonin (5-HT) as the mediator of cardiorespiratory changes elicited by AIH, we verified that ketanserin (5-HT2 antagonist) microinjections in the RTN/pFRG in anesthetized rats, during AIH exposure, prevented the increase in abdominal motor activity (ABD) evoked by AIH (n=5, P<0.05), indicating the involvement of 5-HT2 receptor of RTN/pFRG in the generation of active expiration induced by AIH. We also showed that repeated activation of 5-HT2 receptors (3x every 5 min) in the RTN/pFRG of in situ preparation, using DOI, promoted LTF of the PN, AbN and tSN activities (n=9, P<0.05). Interestingly, the increase in the late-E AbN activity induced by DOI in the RTN/pFRG was critical for the development of sympathetic overactivity during late-E phase (n=9, P<0.05), similarly to the pattern observed in in situ preparations subjected to AIH. Microinjections of vehicle in the RTN/pFRG did not change PN, AbN and tSN activities. The increase in respiratory and sympathetic activities promoted by DOI microinjection in the RTN/pFRG was associated to sensitization/facilitation of CO2- drive to breath, since the exposure to hypocapnia eliminated the respiratory activity in control in situ preparation, but not in preparation that received DOI into the RTN/pFRG (n=9, P<0.05). Furthermore, we verified that the DOI-induced sensitization in the RTN/pFRG, which was determinant for the development of respiratory and sympathetic LTF, also depended on glutamatergic neurotransmission in the RTN/pFRG (n=9, P<0.05), because microinjections of kynurenic acid (glutamate receptor antagonist) were able to eliminate the respiratory and sympathetic LTF. Indeed, we found that glutamatergic neurotransmission of the RTN/pFRG is essential for the generation of active expiration, since kynurenic microinjections in the RTN/pFRFG of control in situ preparations abolished the late-E bursts in AbN and tSN induced by hypercapnia. Altogether, our data indicate that interactions between serotonergic and glutamatergic mechanisms in the RTN/pFRG is an essential mechanism for the occurrence of active expiration and late-E sympathetic overactivity after AIH exposure. Moreover, our findings suggest that the activation of 5-HT2 receptors in the RTN/pFRG modulates the excitation of central chemoreceptors of this area, through sensitization/facilitation of glutamatergic mechanisms. / A exposição a episódios de hipoxemia seguido de reoxigenação, como observado na apneia obstrutiva do sono (AOS), promove aumentos compensatórios na ventilação, na atividade simpática e na pressão arterial (PA), por mecanismos ainda não completamente elucidados. No presente estudo, exploramos os mecanismos centrais envolvidos nas alterações cardiorrespiratórias induzidas pela hipóxia intermitente aguda (HIA; 10 episódios 6-7% O2 por 45 s, a cada 5 min de hiperóxia) em ratos adultos (270-280 g) anestesiados com uretana (1,2 g/Kg, i.p.) e ratos jovens (65-75 g) na preparação in situ coração-tronco cerebral isolados. Em preparações in situ, a HIA promoveu uma facilitação a longo prazo (LTF), com duração de, pelo menos, 1 hora, nas atividades dos nervos frênico (PN), abdominal (AbN) e simpático torácico (tSN) (n=9, P<0,05). Nestes animais, observamos que o aumento da atividade tSN ocorreu, preferencialmente, durante a fase final do ciclo expiratório, denominada de fase E- tardia. Tal aumento da atividade simpática induzido pela HIA mostrou-se associada ao aparecimento de disparos E-tardios na atividade AbN (padrão de expiração ativa). Considerando estudos que envolvem a participação da serotonina (5-HT) como mediador das alterações cardiorrespiratórias induzidas pela HIA, verificamos em ratos anestesiados que microinjeções de ketanserina (antagonista 5-HT2) no RTN/pFRG, durante HIA, preveniram o aumento da atividade motora abdominal (ABD) evocado pela HIA (n=5, P<0,05), indicando a participação dos receptores 5-HT2 do RTN/pFRG na geração de expiração ativa induzida pela HIA. Mostramos também que a ativação repetida dos receptores 5-HT2 (3x a cada 5 min) no RTN/pFRG, com o agonista DOI, promoveram LTF nas atividades PN, AbN e tSN (n=9, P<0,05) em preparações in situ. Interessantemente, o aumento da atividade E-tardia AbN, induzido por DOI no RTN/pFRG, foi determinante para o desenvolvimento de hiperatividade simpática na fase expiratória E-tardia (n=9, P<0,05), semelhante àquela observada em preparações in situ submetidas à HIA. Tal elevação das atividades PN, AbN e tSN não foram observadas após a realização de microinjeção veículo no RTN/pFRG. O aumento nas atividades respiratórias e simpática promovidas pela microinjeção de DOI no RTN/pFRG foi associado a sensibilização/facilitação da atividade respiratória dependente de CO 2, uma vez que a redução do drive respiratório, por meio da exposição à hipocapnia, aboliu a atividade respiratória em preparações in situ controle, mas não em preparações que receberam microinjeções de DOI (n=9, P<0,05). Ademais, mostramos que a sensibilização induzida por DOI no RTN/pFRG, na qual resulta no LTF das atividades respiratória e simpática, dependem da neurotransmissão glutamatérgica também no RTN/pFRG (n=9, P<0,05), uma vez que microinjeções de ácido quinurênico (antagonista dos receptores glutamatérgicos) foram capazes de reverter o LTF respiratório e simpático. De fato, a neurotransmissão glutamatérgica é essencial para a geração do padrão expiratório, em resposta à hipercapnia, uma vez que o microinjeções de ácido quinurênico no RTN/pFRG de ratos controle, durante a exposição à hipercapnia, elimina os disparos E-tardios na atividade simpática e abdominal de preparações in situ. Em conjunto, nossos resultados sugerem uma interação importante entre os mecanismos serotoninérgicos e glutamatérgicos no RTN/pFRG, na qual parece ser determinante para o aparecimento do padrão de expiração ativa e aumento da atividade simpática após à exposição à HIA. Nossos dados sugerem que a ativação dos receptores 5- HT2 do RTN/pFRG modula a excitação das células quimiossensíveis desta região, mediante facilitação de mecanismos glutamatérgicos. / FAPESP: 2014/06.976-2; 2013/17.251-6 / CNPq: 478640/2013-7

Central mechanisms involving aldosterone - mineralocorticoid receptor (MR) activation mediate the increase in sympathetic tone after myocardial infarction (MI). We hypothesized that an increase in cardiac sympathetic activity (CSA) post MI facilitates cardiac sympathetic axonal sprouting, and that central MR blockade attenuates CSA and reduces cardiac sympathetic hyperinnervation post MI. Western blotting and qRT-PCR were used to assess protein and gene expression, and fluorescent immunohistochemistry was used to study changes in sympathetic innervation. Tyrosine hydroxylase (TH) and Norepinephrine transporter protein content in the non-infarcted base of the heart remained unaltered. In contrast, protein gene product (PGP 9.5) protein was significantly increased 2 fold in the base of the heart, and 6 fold in the peri-infarct area at 1 wk post MI, and associated with increased ubiquitin expression. Cardiac myocytes rather than sympathetic axons were identified as the main source of elevated PGP 9.5 expression. At the infarct border sympathetic hyperinnervation was observed with a 4 fold increase in growth associated protein 43 (GAP 43), a 2 fold increase in TH and a 50% increase in PGP 9.5 positive fibers when compared to the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone at 5 ug/day for 9 days post MI markedly attenuated the increase in TH, GAP 43 and PGP 9.5 nerve densities at the infarct border. Central MR blockade may attenuate sympathetic hyperinnervation by several mechanisms, including decreasing CSA post MI, or affecting expression or function of nerve growth factor protein. Marked PGP 9.5 expression occurs in cardiomyocytes early post MI, which may contribute to the increase in ubiquitin and the early cardiac remodeling post MI.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-11T12:25:35Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 23. Dissertação Kássya - BC.pdf: 2666703 bytes, checksum: e183097b30e295d682e56df2e85dd818 (MD5) / Made available in DSpace on 2016-04-11T12:25:35Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 23. Dissertação Kássya - BC.pdf: 2666703 bytes, checksum: e183097b30e295d682e56df2e85dd818 (MD5) Previous issue date: 2015-07-28 / FACEPE / Estudos buscam esclarecer a relação entre desnutrição proteica em fase crítica do desenvolvimento e surgimento de hipertensão arterial na vida adulta, entretanto os mecanismos que participam deste processo ainda não são totalmente conhecidos. Neste estudo investigamos as repercussões da desnutrição proteica perinatal (gestação e lactação) sobre o nível basal e o controle barorreflexo da atividade do sistema nervoso simpático da prole. Ratas prenhes foram alimentadas com dieta hipoproteica (8% de proteína, grupo experimental) ou com dieta normoproteica (17% de proteína, grupo controle) durante o período perinatal. Após o desmame, a prole de ratos machos recebeu dieta padrão para animais de laboratório e os estudos funcionais foram realizados aos 90 dias de vida. Todos os protocolos experimentais foram aprovados pelo comitê de ética em utilização animal da UFPE (processo nº 23076.016256/2013-83). Para registro direto das variáveis hemodinâmicas e infusão das drogas, foram implantadas cânulas na artéria e veia femoral, respectivamente. Os níveis de atividade autonômica foram estimados através de métodos lineares e não lineares de análise da variabilidade da pressão sistólica e intervalo de pulso em animais conscientes e anestesiados, enquanto a eficiência do mecanismo barorreflexo em regular a pressão arterial foi avaliado através de métodos indiretos de sequência espontânea e de forma induzida mediante infusão de fenilefrina e nitroprussiato de sódio. Além disso, foi realizado implante de eletrodo bipolar na cadeia simpática em nível L3-L5 para registro direto da atividade elétrica do nervo lombar em animais anestesiados. Os resultados demonstram que ratos submetidos à desnutrição proteica perinatal apresentam desbalanço autonômico para o coração, com aumento do componente de baixa frequência no espectro da pressão sistólica e intervalo de pulso, aumento do índice simpatovagal para o coração e aumento dos padrões 0V, relacionados ao tônus simpático cardiovascular. Além disso, observamos a integridade do controle barrorreflexo da pressão arterial em todas as doses avaliadas, uma vez que os animais não anestesiados submetidos à restrição proteica apresentaram sensibilidade barorreflexa semelhante aos controles. Em condições de anestesia, o registro direto do nervo lombar em ratos desnutridos não foi diferente dos seus pares, demonstrando que o controle barorreflexo da atividade nervosa simpática lombar está preservado neste modelo experimental. Esses achados apontam que o desenvolvimento da hipertensão arterial na prole submetida à desnutrição proteica perinatal não está relacionada à disfunção do barorreflexo em animais conscientes e anestesiados. Sugerimos que outros mecanismos centrais e periféricos possam estar envolvidos no surgimento e manutenção dos níveis elevados de pressão arterial neste modelo experimental. / Studies seek to clarify the relationship between protein malnutrition in critical stage of development and emergence of hypertension in adulthood, however the mechanisms involved in this process are not yet fully known. We investigated the effects of perinatal protein malnutrition (pregnancy and lactation) on the baseline and the baroreflex control of the sympathetic nervous system activity on the offspring. Pregnant rats were fed a low protein diet (8% protein, experimental group) or normal protein diet (17% protein, control group) during the perinatal period. After weaning, the male offspring of rats received standard diet to laboratory animals and functional studies were performed at 90 days of life. All experimental protocols were approved by the Ethics Committee on Animal use of UFPE (process n° 23076.016256 / 2013-83). For the direct recording of hemodynamic variables and for the infusion of drugs, cannulas were implanted in the femoral artery and vein, respectively. The autonomic activity levels were estimated by linear and nonlinear methods of analysis of the variability of systolic and pulse interval in conscious and anesthetized animals. The efficiency of the baroreflex mechanism in regulating the blood pressure was evaluated by indirect methods of sequence and form spontaneously induced by phenylephrine and sodium nitroprusside infusion. We also performed bipolar electrode implantation in the sympathetic chain at L3-L5 level for direct recording of the electrical activity of the lumbar nerve in anesthetized animals. The results show that rats with perinatal protein malnutrition have autonomic imbalance to the heart, with increased low frequency component in the spectrum of systolic and pulse interval, increased sympathovagal index to the heart and increase the standards 0V, related to the tone cardiovascular friendly. In addition, we observe the integrity of baroreflex control of blood pressure in all evaluated doses, since unanesthetized animals submitted to protein restriction had baroreflex sensitivity similar to controls. In anesthesia conditions, the record of straight lumbar nerve in malnourished rats was not different from their peers, demonstrating that the baroreflex control of lumbar sympathetic nerve activity is preserved in this experimental model. These findings indicate that the development of hypertension in offspring submitted to perinatal protein malnutrition is not related to the baroreflex dysfunction in conscious and anesthetized animals. We suggest that other central and peripheral mechanisms may be involved in the emergence and maintenance of high levels of blood pressure in this experimental model.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-11T15:40:54Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 23. Dissertação Kássya - BC.pdf: 2666703 bytes, checksum: e183097b30e295d682e56df2e85dd818 (MD5) / Made available in DSpace on 2016-04-11T15:40:54Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 23. Dissertação Kássya - BC.pdf: 2666703 bytes, checksum: e183097b30e295d682e56df2e85dd818 (MD5) Previous issue date: 2015-07-28 / FACEPE / Estudos buscam esclarecer a relação entre desnutrição proteica em fase crítica do desenvolvimento e surgimento de hipertensão arterial na vida adulta, entretanto os mecanismos que participam deste processo ainda não são totalmente conhecidos. Neste estudo investigamos as repercussões da desnutrição proteica perinatal (gestação e lactação) sobre o nível basal e o controle barorreflexo da atividade do sistema nervoso simpático da prole. Ratas prenhes foram alimentadas com dieta hipoproteica (8% de proteína, grupo experimental) ou com dieta normoproteica (17% de proteína, grupo controle) durante o período perinatal. Após o desmame, a prole de ratos machos recebeu dieta padrão para animais de laboratório e os estudos funcionais foram realizados aos 90 dias de vida. Todos os protocolos experimentais foram aprovados pelo comitê de ética em utilização animal da UFPE (processo nº 23076.016256/2013-83). Para registro direto das variáveis hemodinâmicas e infusão das drogas, foram implantadas cânulas na artéria e veia femoral, respectivamente. Os níveis de atividade autonômica foram estimados através de métodos lineares e não lineares de análise da variabilidade da pressão sistólica e intervalo de pulso em animais conscientes e anestesiados, enquanto a eficiência do mecanismo barorreflexo em regular a pressão arterial foi avaliado através de métodos indiretos de sequência espontânea e de forma induzida mediante infusão de fenilefrina e nitroprussiato de sódio. Além disso, foi realizado implante de eletrodo bipolar na cadeia simpática em nível L3-L5 para registro direto da atividade elétrica do nervo lombar em animais anestesiados. Os resultados demonstram que ratos submetidos à desnutrição proteica perinatal apresentam desbalanço autonômico para o coração, com aumento do componente de baixa frequência no espectro da pressão sistólica e intervalo de pulso, aumento do índice simpatovagal para o coração e aumento dos padrões 0V, relacionados ao tônus simpático cardiovascular. Além disso, observamos a integridade do controle barrorreflexo da pressão arterial em todas as doses avaliadas, uma vez que os animais não anestesiados submetidos à restrição proteica apresentaram sensibilidade barorreflexa semelhante aos controles. Em condições de anestesia, o registro direto do nervo lombar em ratos desnutridos não foi diferente dos seus pares, demonstrando que o controle barorreflexo da atividade nervosa simpática lombar está preservado neste modelo experimental. Esses achados apontam que o desenvolvimento da hipertensão arterial na prole submetida à desnutrição proteica perinatal não está relacionada à disfunção do barorreflexo em animais conscientes e anestesiados. Sugerimos que outros mecanismos centrais e periféricos possam estar envolvidos no surgimento e manutenção dos níveis elevados de pressão arterial neste modelo experimental. / Studies seek to clarify the relationship between protein malnutrition in critical stage of development and emergence of hypertension in adulthood, however the mechanisms involved in this process are not yet fully known. We investigated the effects of perinatal protein malnutrition (pregnancy and lactation) on the baseline and the baroreflex control of the sympathetic nervous system activity on the offspring. Pregnant rats were fed a low protein diet (8% protein, experimental group) or normal protein diet (17% protein, control group) during the perinatal period. After weaning, the male offspring of rats received standard diet to laboratory animals and functional studies were performed at 90 days of life. All experimental protocols were approved by the Ethics Committee on Animal use of UFPE (process n° 23076.016256 / 2013-83). For the direct recording of hemodynamic variables and for the infusion of drugs, cannulas were implanted in the femoral artery and vein, respectively. The autonomic activity levels were estimated by linear and nonlinear methods of analysis of the variability of systolic and pulse interval in conscious and anesthetized animals. The efficiency of the baroreflex mechanism in regulating the blood pressure was evaluated by indirect methods of sequence and form spontaneously induced by phenylephrine and sodium nitroprusside infusion. We also performed bipolar electrode implantation in the sympathetic chain at L3-L5 level for direct recording of the electrical activity of the lumbar nerve in anesthetized animals. The results show that rats with perinatal protein malnutrition have autonomic imbalance to the heart, with increased low frequency component in the spectrum of systolic and pulse interval, increased sympathovagal index to the heart and increase the standards 0V, related to the tone cardiovascular friendly. In addition, we observe the integrity of baroreflex control of blood pressure in all evaluated doses, since unanesthetized animals submitted to protein restriction had baroreflex sensitivity similar to controls. In anesthesia conditions, the record of straight lumbar nerve in malnourished rats was not different from their peers, demonstrating that the baroreflex control of lumbar sympathetic nerve activity is preserved in this experimental model. These findings indicate that the development of hypertension in offspring submitted to perinatal protein malnutrition is not related to the baroreflex dysfunction in conscious and anesthetized animals. We suggest that other central and peripheral mechanisms may be involved in the emergence and maintenance of high levels of blood pressure in this experimental model.