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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2013.tde-31102013-100352
Document
Author
Full name
Eduardo Albino Trindade Fortaleza
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2013
Supervisor
Committee
Correa, Fernando Morgan de Aguiar (President)
Machado, Benedito Honório
Moreira, Fabrício de Araújo
Pinge, Marli Cardoso Martins
Zangrossi Junior, Helio
Title in Portuguese
Função da neurotransmissão noradrenérgica do núcleo medial da amígdala na modulação do sistema cardiovascular em ratos
Keywords in Portuguese
Estresse por restrição
Frequência cardíaca
Noradrenalina
Núcleo medial da amígdala
Pressão arterial
Abstract in Portuguese
RESUMO FORTALEZA, E. A. T. Função da neurotransmissão noradrenérgica do núcleo medial da amígdala na modulação do sistema cardiovascular em ratos. 2013. 153p. Tese (Doutorado) Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2013. O núcleo medial da amígdala (NMA) está envolvido no controle de uma variedade de processos fisiológicos e comportamentais, dentre eles, a regulação do sistema cardiovascular durante situações aversivas. Além disso, existem evidências indicando a presença de receptores noradrenérgicos no NMA e que os níveis de noradrenalina (NA) no NMA aumentam quando animais são submetidos ao modelo de estresse por restrição (ER). Portanto, o presente estudo foi dividido em duas partes: 1) avaliamos os efeitos da microinjeção local de NA no NMA de ratos, bem como os receptores locais e os mecanismos periféricos envolvidos na sua mediação e 2) investigamos o papel desempenhado pela neurotransmissão noradrenérgica do NMA sobre as respostas cardiovasculares causadas pelo ER. A primeira parte dos nossos resultados indicou que doses crescentes de NA (3, 9, 27 ou 45nmol/100nL) microinjetadas no NMA causavam respostas pressoras e bradicardicas de maneira dose-dependente em ratos não anestesiados. Os efeitos da NA no NMA foram abolidos pelo pré-tratamento local com antagonista de receptores 2-adrenérgicos (RX821002, 10 nmol/100nL), porém não foram alterados pelo pré-tratamento com antagonista de receptores 1adrenérgicos (WB4101, 10 nmol/100nL). A magnitude da resposta pressora à NA no NMA foi aumentada pelo pré-tratamento intravenoso (i.v.) com o bloqueador ganglionar pentolínio (5mg/kg) e foi significativamente reduzida pelo pré-tratamento i.v. com antagonista dos receptores vasopressinérgicos do tipo V1 dTyr(CH2)5(Me)AVP (50 g/Kg) sugerindo que o mecanismo periférico envolvido nestas respostas cardiovasculares é a liberação de vasopressina na circulação sanguínea. Como estruturas finais participando das respostas cardiovasculares desencadeadas pela microinjeção de NA no NMA, foi observado o possível envolvimento dos núcleos paraventricular (NPV) e supra-óptico (NSO) do hipotálamo, que sintetizam vasopressina. O bloqueio de sinapses, tanto no NPV quanto no NSO, com cloreto de cobalto (CoCl2, 1mM/100nL), reduziu as respostas cardiovasculares desencadeadas pela microinjeção de NA no NMA, sugerindo que ambos os núcleos são responsáveis pela liberação de vasopressina em resposta à NA no NMA. Na segunda parte deste estudo, os resultados mostraram que a microinjeção bilateral de WB4101, antagonista seletivo dos receptores 1- adrenérgicos (10, 15 e 20nmol/100nL) no NMA 10 min antes do ER, reduziu a resposta taquicárdica evocada pelo ER, de maneira dose-dependente. Em contraste, a microinjeção bilateral de RX821002, antagonista seletivo dos receptores 2- adrenérgicos (10, 15 e 20nmol/100nL) no NMA 10 min antes do ER, aumentou a resposta taquicárdica evocada pelo ER de maneira dose-dependente. Ambos os tratamentos não causaram alterações na resposta pressora observada nos animais submetidos ao ER. Estes resultados sugerem que receptores 1- e 2-adrenérgicos no NMA desempenham papel facilitatório e inibitório, respectivamente, na resposta taquicárdica durante o ER. Além disso, a microinjeção bilateral de propranolol, antagonista não seletivo dos receptores -adrenérgicos (10, 15 e 20nmol/100nL), no MNA 10 min antes do ER, causou aumento na resposta taquicárdica apenas quando os animais foram pré-tratados com a dose de 15 nmol, sem efeito significativo sobre a resposta pressora observada durante o ER. Este resultado indica que receptores -adrenérgicos no NMA desempenham um papel inibitório sobre a frequência cardíaca durante o ER. Uma vez que foi observada a participação dos receptores - adrenérgicos, realizamos o pré-tratamento com os antagonistas seletivos dos receptores 1- e 2- adrenérgicos, CGP 20712 e ICI 118,551, respectivamente. A microinjeção bilateral de ICI 118,551 (10, 15 e 20nmol/100nL) no NMA aumentou as respostas taquicárdicas ao ER após a microinjeção das doses de 15 e 20 nmol. Esse efeito foi semelhante ao observado após o tratamento prévio com propranolol, na dose de 15 nmol, sem efeito significativo sobre a resposta da pressora durante o ER. Porém, o pré-tratamento com o CGP 20712 (10, 15 e 20 nmol/100 nL) causou um efeito oposto sobre a resposta taquicárdica evocada pelo ER, ocorrendo uma redução da resposta taquicárdica que foi observada apenas após a dose de 20 nmol no NMA, sem efeito significativo sobre a resposta pressora evocada pelo ER. Esses resultados sugerem que os receptores 2-adrenérgicos desempenham influência inibitória sobre a resposta taquicárdica, ao passo que, os receptores 1-adrenérgicos desempenham influência facilitatória na resposta taquicárdica evocada pelo ER.
Title in English
Noradrenergic neurotransmission function of the medial nucleus of the amygdala in the modulation of the cardiovascular system in rats.
Keywords in English
Blood Pressure
Heart rate Medial amygdaloid nucleus
Noradrenaline
Restraint stress
Abstract in English
ABSTRACT FORTALEZA, E. A. T. Noradrenergic neurotransmission function of the medial nucleus of the amygdala in the modulation of the cardiovascular system in rats. 2013. 153p. Thesis (Doctoral) School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 2013. The medial amygdaloid nucleus (MeA) regulates a variety of physiological and behavioral processes, as well as regulation of the cardiovascular system during aversive situations. Moreover, there is evidence indicating that noradrenergic receptors are present into the MeA and that the levels of noradrenaline (NA) in this nucleus increases when animals are submitted to acute restraint model. Therefore, this study was divided into two parts: 1) we tested the effects of local NA microinjection into the MeA on cardiovascular responses in unaesthetized rats. Moreover, we describe the type of adrenoceptors activated and the peripheral mechanisms involved in the cardiovascular responses and 2) we investigated the involvement of MeA adrenoceptors in the modulation of cardiovascular responses that are observed during acute restraint. The first part of our results indicated that increasing doses of NA (3, 9, 27 or 45 nmol/ 100nL) microinjected into the MeA of unanesthetized rats caused dose-related pressor and bradycardiac responses. The cardiovascular effects of NA were abolished by MeA local pretreatment with 10 nmol/ 100nL of the specific 2-adrenoceptor antagonist RX821002, but were not affected by local pretreatment with 10 nmol/100nL of the specific 1-adrenoceptor antagonist WB4101. The magnitude of pressor response evoked by NA microinjected into the MeA was potentiated by intravenous pretreatment with the ganglion blocker pentolinium (5 mg/kg, i.v.) and blocked by intravenous pretreatment with the selective V1 vasopressin antagonist dTyr (CH2)5(Me) AVP (50 g/Kg, i.v.). Our results suggest that microinjection of NA into the MeA of unanesthetized rats activates local 2- adrenoceptors, evoking pressor and bradycardiac responses, which are mediated by vasopressin release in the blood circulation. The vasopressin is synthesized by magnocellular cells of paraventricular (PVN) and supraoptic nucleus (SON) of the hypothalamus. Thus, it was investigated the role of these hypothalamic nucleus on the cardiovascular pathway activated by the microinjection of NA into the MeA. Pressor and bradycardiac responses to NA (27nmol/100nL) were blocked when cobalt chloride (CoCl2, 1mM/100nL) was microinjected into the PVN or SON, thus indicating that both hypothalamic nucleus are responsible for the mediation of the cardiovascular responses evoked by NA microinjection into the MeA. Our results suggest that pressor and bradycardic responses caused by NA microinjection into the MeA are mediated by magnocellular neurons in the PVN and SON. In the second part of this study Male Wistar rats received bilateral microinjections of the selective 1-adrenoceptor antagonist WB4101 (10, 15, and 20 nmoL/100nL) or the selective 2-adrenoceptor antagonist RX821002 (10, 15, and 20 nmoL/nL) into the MeA, 10 min before the exposure to acute restraint. The injection of WB4101 into the MeA reduced the restraint-evoked tachycardia. In contrast, the injection of RX821002 increased the tachycardia. Both drugs had no effect on the BP increase observed during the acute restraint. Our findings indicate that 1 and 2-adrenoceptors in the MeA play different roles in the modulation of the HR increase evoked by restraint stress in rats. Results suggest that 1-adrenoceptors and 2-adrenoceptors respectively mediate the MeA facilitatory and inhibitory influences on restraint-related HR responses. Moreover, we investigated the involvement of -adrenoceptors in the MeA in cardiovascular responses evoked in rats submitted to an acute restraint stress. We first pretreated Wistar rats with the nonselective -adrenoceptor antagonist propranolol, microinjected bilaterally into the MeA (10, 15, and 20 nmol/100nL) 10 min before exposure to acute restraint. The pretreatment with propranolol did not affect the BP increase evoked by restraint. However, it increased the tachycardiac response caused by acute restraint when animals were pretreated with a dose of 15 nmol, without a significant effect on the BP response. This result indicates that -adrenoceptors in the MeA have an inhibitory influence on restraintevoked HR changes. Pretreatment with the selective 2- adrenoceptor antagonist ICI 118,551 (10, 15, and 20 nmol/100 nL) significantly increased the restraint evoked tachycardiac response after the doses of 15 and 20 nmol, an effect that was similar to that observed after the pretreatment with propranolol at the dose of 15 nmol, without a significant effect on the BP response. Pretreatment of the MeA with the selective 1-adrenoceptor antagonist CGP 20712 (10, 15, and 20 nmol/100nL) caused an opposite effect on the HR response, and a significant decrease in the restraint-evoked tachycardia was observed only after the dose of 20nmol, without a significant effect on the BP response. Because propranolol is an equipotent antagonist of both 1 and 2-adrenoceptors, and opposite effects were observed after the treatment with the higher doses of the selective antagonists ICI 118,551 and CGP 20712, the narrow window in the dose-response to propranolol could be explained by a functional antagonism resulting from the simultaneous inhibition of 1 and 2-adrenoceptors by the treatment with propranolol.
 
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2015-05-28
 
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