Avaliação das respostas cardiovasculares e simpáticas promovidas pela injeção de moxonidina no núcleo do trato solitário comissural de rato
Data
2015-03-31
Autores
Alves, Thales Biffe 
Orientadores
Colombari, Eduardo Colombari
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Importantes drogas de ação anti-hipertensiva utilizadas na clínica médica são os agonistas adrenérgicos alfa2 e imidazólicos. Várias evidências têm sugerido que o efeito anti-hipertensivo desses fármacos é mediado, pelo menos em parte, pela ativação de receptores imidazólicos do tipo I1 presentes na região rostroventrolateral (RVL) do bulbo. Resultados do nosso grupo mostraram que a moxonidina pode produzir hipotensão por agir na região do núcleo do trato solitário comissural (NTScom). Experimentos in vitro mostraram que os efeitos hiperpolarizantes produzidos pela clonidina eram abolidos após a aplicação prévia do antagonista de receptores GABA-A bicuculina. Ademais, alguns trabalhos na literatura demonstraram que o bloqueio de receptores glutamatérgicos ionotrópicos no RVL foi capaz de prevenir a hipotensão produzida pela rilmenidina em ratos espontaneamente hipertensos. Desse modo, a nossa hipótese foi que a moxonidina, atuando em neurônios do NTScom e mediante sua ação integrada com receptores GABAérgicos e glutamatérgicos, poderia exercer os seus efeitos de hipotensão e simpato-inibição. Para isso, foram registrados a pressão arterial media e a atividade simpática do nervo esplâncnico. Foram utilizados ratos Wistar (250-350g, n = 6/grupo) anestesiados com uretano (1,2 g/kg, iv) e ventilados artificialmente. Nossos resultados evidenciaram que a injeção do antagonista de receptores adrenérgicos alfa2 ioimbina (10 nmol/50 nl) no NTScom foi capaz de bloquear as respostas hipotensora (Delta = -3 ± 2 mmHg, vs. moxonidina: Delta = -22 ± 4 mmHg) e a simpatoinibição (Delta = -2 ± 5%, vs. moxonidina: Delta = -26 ± 3% do basal) produzida pela injeção de moxonidina (5 nmol/50 nl) no NTScom. Similarmente, a injeção do antagonista de receptores GABAérgicos do sub-tipo A bicuculina (25 pmol/50 nl) na região do NTScom atenuou a hipotensão (Delta = -11 ± 3, vs. moxonidina: -28 ± 5 mmHg) e a simpatoinibição (Delta = - 13 ± 3% vs. moxonidina: Delta = -24 ± 2% do basal) promovida pela injeção de moxonidina no NTScom. Contudo, a administração do antagonista de receptores glutamatérgicos ionotrópicos ácido quinurênico (2,5 nmol/50 nl) na região do NTScom não foi efetivo em atenuar a hipotensão (Delta = -24 ± 3, vs. moxonidina: Delta = - 25 ± 9 mmHg) e a simpatoinibição (Delta = -22 ± 5% vs. moxonidina: Delta = -28 ± 9%, do basal) promovida pela injeção de moxonidina no NTScom. Os nossos resultados mostram também que as respostas hipotensoras e simpatoinibitórias promovidas pela injeção de moxonidina no NTScom não dependem da integridade dos neurônios catecolaminérgicos bulbo espinais da região rostroventrolateral do bulbo, sugerindo que os neurônios C1 não são essenciais para as respostas de redução da PA e atividade simpática exercida pela moxonidina. Assim, os efeitos anti-hipertensivos da moxonidina parecem carecer de mecanismos adrenérgicos alfa2 e GABAérgicos, mas não glutamatérgicos, pelo menos ionotrópicos, para exercer de forma significante o efeito hipotensor e simpatoinibitório.
Important antihypertensive drugs used in clinical medicine are the alpha2 adrenergic and imidazoline (I1) agonists. Several studies have suggested that antihypertensive effect is mediated, in part by I1 receptors in the rostroventrolateralmedula (RVL). Previous results from our laboratory elicited that moxonidine can also act in commissural nucleus of solitary tract (comNTS). Some studies have shown that glutamatergic receptor antagonist in RVL prevented the hypotension produced by rilmenidine in spontaneous hypertensive rats. Therefore, it would be interesting to investigate whether the cardiovascular and sympathetic effects produced by moxonidine in comNTS are dependent of glutamatergic mechanisms. Also, in vitro studies elicited hyperpolarizing effects carried out by clonidine were abolished after injection of GABA-A receptor antagonist previously. Thereby, it would be interesting to verify whether the cardiovascular and sympathetic effects produced by moxonidine in comNTS are dependent of GABAergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethaneanesthetized(1.2 g/kg, iv), and artificial ventilated male Wistar rats (250-350 g, n = 6/group). The injection of the alpha2-adrenergic receptor antagonist yohimbine (10 nmol/50 ml) into the commNTS blocked the hypotension (Delta = -3 ± 2 mmHg, vs. moxonidine: Delta = -22 ± 4 mmHg) and the reduction in sSNA (Delta = -2 ± 5 %, vs. moxonidine: Delta = -26 ± 3%) elicited by moxonidine (5 nmol/50 nl). Similarly, previous injection of GABA-A antagonist bicuculline (25 pmol/50 nl) into comNTS reduced the hypotension (Delta = -11 ± 3, vs. moxonidine: Delta = -28 ± 5 mmHg) as well as sympathoinhibition (Delta = -13 ± 3% vs. moxonidine: Delta = -24 ± 2%) elicited by moxonidine. Nevertheless, previous injection of glutamatergic antagonist kynurenic acid (2.5 nmol/50 nl) into comNTS was not effective in reducing the hypotension (Delta = -24 ± 3, vs. moxonidina: Delta = -25 ± 9 mmHg) and sympathoinhibition (Delta = -22 ± 5% vs. moxonidina: Delta = -28 ± 9%, do basal) elicited by moxonidine. Our data data also show that although moxonidine inhibits presympathetic C1 neurons, bulbospinal catecholaminergic neurons do not appear to be essential for the sympatholytic and hypotensive effects of NTS administered moxonidine. Therefore, we conclude that antihypertensive effects elicited by moxonidine into comNTS are dependent of alpha2- adrenergic and GABAergic mechanisms, but not glutamatergic, at least ionotropic, to exert the reduction in arterial pressure and sympathetic nerve activity.
Important antihypertensive drugs used in clinical medicine are the alpha2 adrenergic and imidazoline (I1) agonists. Several studies have suggested that antihypertensive effect is mediated, in part by I1 receptors in the rostroventrolateralmedula (RVL). Previous results from our laboratory elicited that moxonidine can also act in commissural nucleus of solitary tract (comNTS). Some studies have shown that glutamatergic receptor antagonist in RVL prevented the hypotension produced by rilmenidine in spontaneous hypertensive rats. Therefore, it would be interesting to investigate whether the cardiovascular and sympathetic effects produced by moxonidine in comNTS are dependent of glutamatergic mechanisms. Also, in vitro studies elicited hyperpolarizing effects carried out by clonidine were abolished after injection of GABA-A receptor antagonist previously. Thereby, it would be interesting to verify whether the cardiovascular and sympathetic effects produced by moxonidine in comNTS are dependent of GABAergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethaneanesthetized(1.2 g/kg, iv), and artificial ventilated male Wistar rats (250-350 g, n = 6/group). The injection of the alpha2-adrenergic receptor antagonist yohimbine (10 nmol/50 ml) into the commNTS blocked the hypotension (Delta = -3 ± 2 mmHg, vs. moxonidine: Delta = -22 ± 4 mmHg) and the reduction in sSNA (Delta = -2 ± 5 %, vs. moxonidine: Delta = -26 ± 3%) elicited by moxonidine (5 nmol/50 nl). Similarly, previous injection of GABA-A antagonist bicuculline (25 pmol/50 nl) into comNTS reduced the hypotension (Delta = -11 ± 3, vs. moxonidine: Delta = -28 ± 5 mmHg) as well as sympathoinhibition (Delta = -13 ± 3% vs. moxonidine: Delta = -24 ± 2%) elicited by moxonidine. Nevertheless, previous injection of glutamatergic antagonist kynurenic acid (2.5 nmol/50 nl) into comNTS was not effective in reducing the hypotension (Delta = -24 ± 3, vs. moxonidina: Delta = -25 ± 9 mmHg) and sympathoinhibition (Delta = -22 ± 5% vs. moxonidina: Delta = -28 ± 9%, do basal) elicited by moxonidine. Our data data also show that although moxonidine inhibits presympathetic C1 neurons, bulbospinal catecholaminergic neurons do not appear to be essential for the sympatholytic and hypotensive effects of NTS administered moxonidine. Therefore, we conclude that antihypertensive effects elicited by moxonidine into comNTS are dependent of alpha2- adrenergic and GABAergic mechanisms, but not glutamatergic, at least ionotropic, to exert the reduction in arterial pressure and sympathetic nerve activity.
Descrição
Citação
ALVES, Thales Biffe. Avaliação das respostas cardiovasculares e simpáticas promovidas pela injeção de moxonidina no núcleo do trato solitário comissural de rato. 2015. 107 f. Tese (Doutorado em Farmacologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.