Contribuição das neurotransmissões excitatórias nos núcleos pré-óptico mediano e paraventricular do hipotálamo na modulação da atividade nervosa simpática renal e esplâncnica
| dc.contributor.advisor-co1 | Toney, Glenn M. | |
| dc.contributor.advisor1 | Pedrino, Gustavo Rodrigues | |
| dc.contributor.advisor1Lattes | http://lattes.cnpq.br/1155446449250341 | pt_BR |
| dc.contributor.referee1 | Pedrino, Gustavo Rodrigues | |
| dc.contributor.referee2 | Cavasin, Gláucia Maria | |
| dc.contributor.referee3 | Mendes, Elizabeth Pereira | |
| dc.contributor.referee4 | Rosa, Daniel Alves | |
| dc.contributor.referee5 | Rebelo, Ana Cristina Silva | |
| dc.creator | Mourão, Aline Andrade | |
| dc.creator.Lattes | http://lattes.cnpq.br/1596884578398481 | pt_BR |
| dc.date.accessioned | 2022-07-06T10:49:48Z | |
| dc.date.available | 2022-07-06T10:49:48Z | |
| dc.date.issued | 2018-09-20 | |
| dc.description.abstract | The increase of sympathetic nervous activity (SNA) stands out as the main aggravating factor for diseases related to the cardiovascular system, as well arterial hypertension (AH). In fact, several research groups have directed their studies to the understanding of how alterations of regions and nuclei located in the central nervous system (CNS) could result in sympathetic hyperactivity and, consequently, the development and maintenance of AH. Cardiovascular control regions such as the median preoptic nucleus (MnPO) and the paraventricular nucleus (PVN) of the hypothalamus have been the focus of important investigations on the involvement of the CNS in the physiopathology of AH. However, signaling pathways that can modulate the neurons of these nuclei still need to be clarified. Therefore, the first part of this study aimed to investigate the involvement of angiotensinergic and glutamatergic neurotransmissions in the MnPO on the sympathetic activity and blood pressure increases observed in hypertensive rats. Spontaneously hypertensive rats (SHR) and rats submitted previously to the Goldblatt protocol (two kidneys; one clip; 2K1C) were used. Rats of both groups (250 to 350g, n=6) were anesthetized with urethane (1.2g/kg,i.v.) and instrumented to record mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA). Nanoinjection (100nl) of saline (NaCl, 150 mM), Losartan (AT1 receptor antagonist; 10mM) and kynurenic acid (glutamate receptor antagonist; 50mM) into the MnPO were performed. In 2K1C rats, glutamatergic blockade promoted decreases in MAP and RSNA (-19.1 ± 0.9 mmHg, -21.6 ± 2.8 %, p< 0.05) when compared to saline (-0.4 ± 0.6 mmHg, 0.2 ± 0.7 %, p < 0.05). Angiotensinergic inhibition also reduced these parameters (-11.5 ± 1.2 mmHg, -10.5 ± 1.0 %, p < 0.05) in 2K1C. In SHR, Kynurenic acid nanoinjections produced hypotension and sympathoinhibition (-21.0 ± 2.5 mmHg, -24.7 ± 2.4 %, p < 0.05), as well Losartan nanoinjections (-9.7 ± 1.2 mmHg; p < 0.05) and RSNA (-12.0 ± 2.4 %, p < 0.05). These findings support the conclusion that a tonic excitatory neurotransmission exerted by angiotensin II, and mostly by glutamate in the MnPO are involved in the elevation of blood pressure and RSNA observed in models of genetic hypertension or secondary to renal artery stenosis. In the second part of this study, we tested the hypothesis that the pro-inflammatory cytokine (PIC) tumor necrosis factor alpha (TNFα) could acutely activate the PVN neurons to promote SNA increased. For that purpose, Sprague-Dawley rats (350-550g) were anesthetized with a mixture of α-chloralose (80 mg / kg) and urethane (800 mg / kg) and instrumented for MAP, HR, splanchnic SNA (SSNA) recordings and unilateral nanoinjections in PVN. The animals were submitted to series of experiments with the following pretreatments in the PVN: vehicle (PBS, 0.5 nmol / 50 nl, n = 5), NBQX (AMPA receptor antagonist; 5.2 nmol / 50 nl n = 5) and AP5 (NMDA receptor antagonist; 24 nmol / 50 nl, n = 5). After each pretreatment, nanoinjection of TNFα (0.6 pmol / 50 nl) was performed and cardiovascular and sympathetic variables, evaluated for 60 min. TNFα nanoinjections in the PVN promoted progressive ramp-like increase of SSNA (55 ± 5.5 %) when pretreated with vehicle (3 ± 3 %, p < 0.05). However, no changes were observed in MAP (95 ± 8 mmHg vs. 94.5 ± 6.2 mmHg) and HR (400.2 bpm ± 13.5 vs. 377 ± 9 bpm) in this group. On the other hand, the blockade of ionotropic glutamate receptors AMPAR and NMDAR promoted reduction in the sympathoexcitatory response (24 ± 5% and 32 ± 6.5%, respectively) induced by the TNFα in the PVN. No changes in cardiovascular parameters were observed in these groups (NBQX: 93 ± 9 mmHg and 429 ± 10 bpm, AP5: 104 ± 3 mmHg and 439 ± 29 bpm). The following experiments sought to investigate the role of NMDA and AMPA in the maintenance of splanchnic sympathoexcitation caused by TNFα nanoinjections in the PVN. Thus, vehicle nanoinjections (PBS, 0.5 nmol / 50 nl, n = 3), NBQX (5.2 nmol / 50 nl, n = 5) and AP5 (24 nmol / 50 nl, n = 4) after 60 min of the TNFα nanoinjection in the PVN. The evaluated parameters were then recorded for additional 60 min. Post treatments did not promote significant alterations in any of the evaluated variables, suggesting that these receptors are not important in maintaining the sympathoexcitation triggered by the administration of TNFα in PVN. Finally, we evaluated whether the PVN inhibition could influence the maintenance of the sympathoexcitation induced by the TNFα. Thus, unilateral nanoinjections of the GABAA receptor agonist, muscimol (1 nmol / 50 nl, n = 5) were performed after 60 min of the TNFα nanoinjections in the PVN. Activation of GABAA receptors in PVN reversed TNFα-induced splanchnic sympathoexcitation from 173 ± 11% to 106 ± 5%, (p < 0.05). The results found in the present study indicate that the development of SSNA increase promoted by TNFα in the PVN is dependent of the ionotropic glutamate receptors AMPAR and NMDAR in this nucleus. Together these findings indicate the importance of glutamatergic neurotransmission in PVN for the generation of the sympathoexcitatory response triggered by neuroinflammation induced by (TNFα) in this nucleus. the MnPO are involved in the elevation of blood pressure and RSNA observed in models of genetic hypertension or secondary to renal artery stenosis. In the second part of this study, we tested the hypothesis that the pro-inflammatory cytokine (PIC) tumor necrosis factor alpha (TNFα) could acutely activate the PVN neurons to promote SNA increased. For that purpose, Sprague-Dawley rats (350-550g) were anesthetized with a mixture of α-chloralose (80 mg / kg) and urethane (800 mg / kg) and instrumented for MAP, HR, splanchnic SNA (SSNA) recordings and unilateral nanoinjections in PVN. The animals were submitted to series of experiments with the following pretreatments in the PVN: vehicle (PBS, 0.5 nmol / 50 nl, n = 5), NBQX (AMPA receptor antagonist; 5.2 nmol / 50 nl n = 5) and AP5 (NMDA receptor antagonist; 24 nmol / 50 nl, n = 5). After each pretreatment, nanoinjection of TNFα (0.6 pmol / 50 nl) was performed and cardiovascular and sympathetic variables, evaluated for 60 min. TNFα nanoinjections in the PVN promoted progressive ramp-like increase of SSNA (55 ± 5.5 %) when pretreated with vehicle (3 ± 3 %, p < 0.05). However, no changes were observed in MAP (95 ± 8 mmHg vs. 94.5 ± 6.2 mmHg) and HR (400.2 bpm ± 13.5 vs. 377 ± 9 bpm) in this group. On the other hand, the blockade of ionotropic glutamate receptors AMPAR and NMDAR promoted reduction in the sympathoexcitatory response (24 ± 5% and 32 ± 6.5%, respectively) induced by the TNFα in the PVN. No changes in cardiovascular parameters were observed in these groups (NBQX: 93 ± 9 mmHg and 429 ± 10 bpm, AP5: 104 ± 3 mmHg and 439 ± 29 bpm). The following experiments sought to investigate the role of NMDA and AMPA in the maintenance of splanchnic sympathoexcitation caused by TNFα nanoinjections in the PVN. Thus, vehicle nanoinjections (PBS, 0.5 nmol / 50 nl, n = 3), NBQX (5.2 nmol / 50 nl, n = 5) and AP5 (24 nmol / 50 nl, n = 4) after 60 min of the TNFα nanoinjection in the PVN. The evaluated parameters were then recorded for additional 60 min. Post treatments did not promote significant alterations in any of the evaluated variables, suggesting that these receptors are not important in maintaining the sympathoexcitation triggered by the administration of TNFα in PVN. Finally, we evaluated whether the PVN inhibition could influence the maintenance of the sympathoexcitation induced by the TNFα. Thus, unilateral nanoinjections of the GABAA receptor agonist, muscimol (1 nmol / 50 nl, n = 5) were performed after 60 min of the TNFα nanoinjections in the PVN. Activation of GABAA receptors in PVN reversed TNFα-induced splanchnic sympathoexcitation from 173 ± 11% to 106 ± 5%, (p < 0.05). The results found in the present study indicate that the development of SSNA increase promoted by TNFα in the PVN is dependent of the ionotropic glutamate receptors AMPAR and NMDAR in this nucleus. Together these findings indicate the importance of glutamatergic neurotransmission in PVN for the generation of the sympathoexcitatory response triggered by neuroinflammation induced by (TNFα) in this nucleus. | eng |
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| dc.description.resumo | O aumento de atividade nervosa simpática (ANS) destaca-se como um dos principais agravantes para as doenças relacionadas ao sistema cardiovascular, como a hipertensão arterial (HA). De fato, diversos grupos de pesquisa têm direcionado seus estudos para o entendimento de como alterações de regiões e núcleos localizados no sistema nervoso central (SNC), poderiam resultar na hiperatividade simpática e, consequente, desenvolvimento e manutenção da HA. Regiões de controle cardiovascular como o núcleo pré-óptico mediano (MnPO) e o núcleo paraventricular (PVN) do hipotálamo tem sido foco de importantes investigações sobre a participação do SNC na fisiopatologia da HA. No entanto, as vias de sinalização que possam modular os neurônios desses núcleos ainda precisam ser esclarecidas. Assim, a primeira parte deste estudo teve como objetivo investigar envolvimento das neurotransmissões glutamatérgica e angiotensinérgica do MnPO nos aumentos da atividade simpática e pressão arterial observados em ratos hipertensos. Para tanto, ratos espontaneamente hipertensos (SHR) e ratos submetidos previamente ao protocolo de Goldblatt (dois rins; um clipe; 2R1C) foram utilizados. Os ratos de ambos os grupos (250 a 350g, n = 6) foram anestesiados com uretano (1,2g / kg, i.v.) e instrumentalizados para registros de pressão arterial média (PAM), frequência cardíaca (FC) e atividade nervosa simpática renal (ANSR). Nanoinjeções (100nl) de salina (NaCl, 150 mM), Losartan (antagonista do receptor AT1; 10mM) e ácido quinurênico (antagonista dos receptores de glutamato; 50mM), foram realizadas no MnPO. Em ratos 2R1C, o bloqueio glutamatérgico promoveu diminuição da PAM e ANSR (-19,1 ± 0,9 mmHg, -21,6 ± 2,8 %, p < 0,05) quando comparado com as nanoinjeções de salina (-0,4 ± 0,6 mmHg, 0,2 ± 0,7 %, p < 0,05). A inibição angiotensinérgica também reduziu esses parâmetros (-11,5 ± 1,2 mmHg, -10,5 ± 1,0 %, p < 0,05) em 2R1C. Em SHR, as nanoinjeções de ácido quinurênico produziram quedas da PAM e ANSR (-21,0 ± 2,5 mmHg, -24,7 ± 2,4 %, p < 0,05), bem como nanoinjeções de Losartan (-9,7 ± 1,2 mmHg; p < 0,05) e ANSR (-12,0 ± 2,4 %, p < 0,05). Os resultados observados suportam a conclusão de que uma neurotransmissão tônica excitatória exercida pela angiotensina II, e, principalmente, pelo glutamato no MnPO, estão envolvidos na elevação da pressão arterial e ANSR observados em modelos de hipertensão genética ou secundária à estenose na artéria renal. Na segunda parte do presente estudo, nós testamos a hipótese de que a citocina pró-inflamatória (CIP) fator de necrose tumoral alfa (TNFα) poderia ativar os neurônios do PVN de forma aguda para promover aumento da ANS. Para tanto, ratos Sprague-Dawley (350-550g) foram anestesiados com uma mistura dos anestésicos α-cloralose (80 mg / kg) e uretano (800 mg / kg) e instrumentalizados para os registros de PAM, FC, ANS esplâncnica (ANSS) e nanoinjeções unilaterais no PVN. Inicialmente os animais passaram por séries de experimentos com os seguintes pré-tratamentos no PVN: veículo (PBS, 0,5 nmol / 50 nl, n = 5), NBQX (antagonista do receptor AMPA; 5,2 nmol / 50 nl, n = 5) e AP5 (antagonista de receptor NMDA; 24 nmol / 50 nl, n = 5). Após cada pré-tratamento foi realizada nanoinjeção de TNFα (0,6 pmol / 50 nl) e as variáveis cardiovasculares e simpáticas foram avaliadas por 60 min. As nanoinjeções de TNFα no PVN promoveram progressivo aumento da ANSS (55 ± 5,5 %) quando previamente tratado com veículo. No entanto, não foram observadas alterações na PAM (95 ± 8 mmHg vs. 94,5 ± 6,2 mmHg) e na FC (400,2 ± 13,5 bpm vs. 377 ± 9 bpm) neste grupo. Por outro lado, o pré-bloqueio dos receptores ionotrópicos de glutamato, AMPAR e NMDAR promoveram reduções na resposta simpatoexcitatória (24 ± 5 % e 32 ± 6,5 %, respectivamente) induzida pela nanoinjeção de TNFα no PVN. Nesses grupos também não foram observadas alterações nos parâmetros cardiovasculares (NBQX: 93 ± 9 mmHg e 429 ± 10 bpm; AP5: 104 ± 3 mmHg e 439 ± 29 bpm). Os experimentos seguintes buscaram então investigar o papel dos receptores NMDA e AMPA na manutenção da simpatoexcitação esplâncnica causado pela nanoinjeção de TNFα no PVN. Assim, foram realizadas nanoinjeções de veículo (PBS, 0,5 nmol / 50 nl, n = 3), NBQX (5,2 nmol / 50 nl, n = 5) e AP5 (24 nmol / 50 nl, n = 4) após 60 min da nanoinjeção de TNFα no PVN. Os parâmetros avaliados foram então registrados por 60 min adicionais. Os pós-tratamentos não promoveram alterações significativas em nenhuma das variáveis avaliadas, o que sugere que esses receptores não possuem importância na manutenção da simpatoexcitação desencadeada pela administração do TNFα no PVN. Finalmente, avaliamos se a inibição do PVN poderia influenciar na manutenção da simpatoexcitação induzida por TNFα. Para isto, foram realizadas nanoinjeções unilaterais do agonista dos receptores GABAA, muscimol (1 nmol / 50 nl, n=5) após 60 min das nanoinjeções de TNFα no PVN. A ativação dos receptores GABAA no PVN, reverteu a simpatoexcitação esplâncnica induzida por TNFα de 173 ± 11 % para 106 ± 5 %, (p < 0,05). Os dados encontrados no presente estudo indicam que o desenvolvimento do aumento da ANSS promovido pelo TNFα no PVN é dependente da ativação dos receptores ionotrópicos de glutamato, AMPAR e NMDAR neste núcleo. Em conjunto estes achados indicam a importância da neurotransmissão glutamatérgica no PVN para a geração da resposta simpatoexcitatória desencadeada pela neuro-inflamação induzida por (TNFα) neste núcleo. | pt_BR |
| dc.description.sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES | pt_BR |
| dc.identifier.citation | MOURÃO, A. A. Contribuição das neurotransmissões excitatórias nos núcleos pré-óptico mediano e paraventricular do hipotálamo na modulação da atividade nervosa simpática renal e esplâncnica. 2018. 134 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2018. | pt_BR |
| dc.identifier.uri | http://repositorio.bc.ufg.br/tede/handle/tede/12164 | |
| dc.language | por | pt_BR |
| dc.publisher | Universidade Federal de Goiás | pt_BR |
| dc.publisher.country | Brasil | pt_BR |
| dc.publisher.department | Instituto de Ciências Biológicas - ICB (RG) | pt_BR |
| dc.publisher.initials | UFG | pt_BR |
| dc.publisher.program | Programa de Pós-graduação em Ciências Biológicas (ICB) | pt_BR |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
| dc.subject | MnPO | por |
| dc.subject | 2R1C | por |
| dc.subject | SHR | por |
| dc.subject | Angiotensina II | por |
| dc.subject | Glutamato | por |
| dc.subject | Simpatoexcitação | por |
| dc.subject | TNFα | por |
| dc.subject | PVN | por |
| dc.subject | Angiotensin II | eng |
| dc.subject | Glutamate | eng |
| dc.subject | Sympathoexcitation | eng |
| dc.subject.cnpq | CIENCIAS BIOLOGICAS::FARMACOLOGIA | pt_BR |
| dc.title | Contribuição das neurotransmissões excitatórias nos núcleos pré-óptico mediano e paraventricular do hipotálamo na modulação da atividade nervosa simpática renal e esplâncnica | pt_BR |
| dc.title.alternative | Contribution of the excitatory neurotransmissions in the median preoptic and paraventricular of the hypothalamus nuclei on the renal and splanchnic sympathetic nerve activity modulation | eng |
| dc.type | Tese | pt_BR |
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